Gasdermins in Innate Host Defense Against Entamoeba histolytica and Other Protozoan Parasites

Abstract

Gasdermins (GSDMs) are a group of proteins that are cleaved by inflammatory caspases to induce pore formation in the plasma membrane to cause membrane permeabilization and lytic cell death or pyroptosis. All GSDMs share a conserved structure, containing a cytotoxic N-terminal (NT) pore-forming domain and a C-terminal (CT) repressor domain. Entamoeba histolytica (Eh) in contact with macrophages, triggers outside-in signaling to activate inflammatory caspase-4/1 via the noncanonical and canonical pathway to promote cleavage of gasdermin D (GSDMD). Cleavage of GSDMD removes the auto-inhibition that masks the active pore-forming NT domain in the full-length protein by interactions with GSDM-CT. The cleaved NT-GSDMD monomers then oligomerize to form pores in the plasma membrane to facilitate the release of IL-1β and IL-18 with a measured amount of pyroptosis. Pyroptosis is an effective way to counteract intracellular parasites, which exploit replicative niche to avoid killing. To date, most GSDMs have been verified to perform pore-forming activity and GSDMD-induced pyroptosis is rapidly emerging as a mechanism of anti-microbial host defence. Here, we review our comprehensive and current knowledge on the expression, activation, biological functions, and regulation of GSDMD cleavage with emphases on physiological scenario and related dysfunctions of each GSDM member as executioner of cell death, cytokine secretion and inflammation against Eh and other protozoan parasitic infections.

Introduction

The gastrointestinal tract encounters innumerable luminal insults, including those caused by noxious substances, commensal bacteria, and/or pathogens. The enteric protozoan parasite Entamoeba histolytica (Eh) is the causative agent of intestinal amebiasis, which manifests as amebic colitis and amebic liver abscess (1, 2) and is named for its ability to lyse host tissues. Of approximately 10 individuals that are infected, one will develop symptoms such as diarrhea and abdominal pain (3). On rare circumstances, Eh penetrates the intestinal mucosa and cause necrosis that extend to the submucosa and muscularis, causing “flask-shaped ulcer” (3, 4) and enter the bloodstream and disseminate to other extraintestinal sites, most commonly the liver, lung and brain. Collectively, there are approximately 100 million annual cases of amebic dysentery, colitis and liver abscess resulting 11,300 deaths in 2013 (5).

The first line of innate host defence in the gastrointestinal tract is the mucus layer produced by goblet cells (6). In the colon, the epithelial barrier consists of three layers: the single layer of intestinal epithelial cells (IECs) that separates the underlying lamina propria, the mucus bilayer and indigenous microbiota that reside in/on the mucus layer (7). The colonic mucus layer contains two components: a firm sterile inner mucus layer adherent on the apical surface of IECs (8), and a superficial loose outer mucus layer that is heavily colonized by commensal microorganisms (9) (Figure 1A). Colonic MUC2 mucins are the structural component of the mucus gel that are rich in galactose (Gal) and N-acetyl galactosamine (GalNAc) (11). Eh colonizes the gut by binding of the surface Gal/GalNAc adherence lectin (Gal-lectin) adhesin to mucin Gal and GalNAc glycans. Here it also uses the Gal-lectin adhesin to bind bacteria and host cells that it feeds upon (12–15). In disease pathogenesis, Eh cysteine proteases degrades peptides in the poor glycosylated regions of the MUC2 C-terminus (16) to abrogate mucus protective functions allowing the parasite to penetrate through the mucus layer (17) (Figure 1B). In addition to mucin degradation, Eh also evokes hypersecretion (exocytosis) of mucus by engaging Eh cysteine protease-5 (EhCP-A5) RGD motif (arginine-glycine-aspartate) to α_vβ₃ integrin on goblet cells (18) as a means not only to defend against the parasite but also to deplete intracellular mucin stores.

Figure 1

When the mucus barrier is degraded and/or depleted by mucus hypersecretion that exceeds MUC2 biosynthesis, Eh comes in contact with and disrupts the surface epithelium. This allows Eh to interact with resident macrophages in the lamina propria to elicit a robust pro-inflammatory response through activation of the nucleotide-binding oligomerization domain (NOD)-like receptor-pyrin containing 3 (NLRP3) inflammasome, leading to interleukin (IL)-1β and IL-18 release (10) (Figure 2A). The direct sensing of Eh via Gal-lectin induces NLRP3 inflammasome activation, driving the processing and release of IL-1β and an aggressive inflammatory response that are aimed at eradicating Eh and recruiting immune cells to the site of infection (10). The canonical NLRP3 inflammasomes are the cytosolic sensor that target pathogens and various cellular stresses that form multimeric high molecular complexes to mediate recruitment and activation of caspase-1 (24). Until recently, most work on the NLRP3 inflammasome has been focused on the functions of caspase-1 (25–29). However, recent studies using Casp1^–/– mice that have a mutation in Casp11, led to the discovery of the noncanonical inflammasome pathway regulated by caspase-11 and identification of a lytic cell death pathway induced by caspase-11 independent of the canonical NLRP3 inflammasome complex (30). Most gram-negative bacteria such as Escherichia coli, Citrobacter rodentium and Vibrio cholerae, activate caspase-11/4-mediated signaling pathway in mouse/human macrophages resulting in maturation and release of IL-1β/IL-18 and pyroptosis (30) (Figure 2B). However, the precise role of caspase-11/4 in macrophage inflammasome signaling and their mechanism of activation against parasitic infections remain to be clarified.

Figure 2

Although caspases have different effector functions, all caspases share a common structure: caspases constitute an N-terminal (NT) pro-domain, a central large domain containing an active cysteine residue and a small C-terminal (CT) subunit domain (31). The pro-domains of caspases contain caspase activation and recruitment domains (CARDs) or death effector domains (DEDs). A growing body of literature suggests that the activation of inflammatory caspase requires at least two steps: the catalytic component of two pro-caspases need to undergo dimerization, which is made up of two large and two small subunits (Figure 3). Following this, autocleavage is triggered within the dimerized full protease (32). Auto-proteolytic processing of pro-caspase occurs when the protein is cleaved between the pro-domain and the large subunit as well as between the large subunit and the small subunit, which allows both large/small subunits to re-assemble as an active heterotetramer (31) (Figure 3). Caspases need to be tightly regulated as their hyperactivation can promote auto-inflammatory diseases, while insufficient activation of caspases can lead to susceptibility to infection and sepsis (33). It is still unclear how each specific caspase works, if there is any redundancy or interaction among them and how caspase functions are fine-tuned.

Figure 3

Upon sensing multiple pathogen and host-derived cellular insults via pathogen and damage-associated molecular patterns (PAMPs and DAMPs, respectively), canonical NLRP3 sensor triggers oligomerization of the adaptor protein apoptosis-associated speck like protein containing a CARD (ASC) and the effector protein caspase-1 through homotypic interactions, leading to the formation of the multimeric inflammasome complex to regulate cytokine maturation and pyroptosis. Yet, the accurate mechanism and interaction governing the crosstalk between canonical NLRP3 and noncanonical caspase-4/5/11 inflammasomes in response to parasites require further elucidation. It has been suggested that caspase-4 and caspase-5 may have originated from caspase-11 (34) as caspase-11 share approximately 60% amino acid identity to caspase-4 (35). Hence, there is a degree of crosstalk between the inflammatory caspases that determine the fate of the cell, and manage the outcome of host response to infections. Macrophages deficient in caspase-4 have decreased caspase-1 activation and reduced IL-1β secretion (22) when stimulated with ATP and monosodium urate crystals (MSU) (36), suggesting caspase-4 functions similarly to caspase-11, as it might regulate caspase-1 activation. The distinct role of caspase-4 is also implicated in dengue virus infection where it was discovered to be critical in regulating caspase-1 activity and subsequent IL-1β secretion (37). By serendipitous discovery, caspase-11 and the human ortholog caspase-4 are shown to directly bind lipopolysaccharide (LPS) via their CARD domains that undergo oligomerization and activation (38). Though caspases are known to require the assembly of receptor complex for their activation, caspase-11 and caspase-4 appear to occur without the formation of a specific receptor complex. Cytosolic LPS released from gram-negative bacteria is detected by murine caspase-11 or human caspase-4 and 5, leading to activation of the noncanonical inflammasome (Figure 2B). These activated inflammatory caspases in turn, cleave GSDMD to cause cell pyroptosis. Similar to macrophages, caspase-4/1 initiate pyroptotic cell death in epithelial cells infected with S. typhimurium to restrict bacterial growth (39). These studies show that caspase-4 activation is important for inflammatory signaling processes, displaying diverse functions, however, extensive studies are required to decipher caspase-4 and caspase-11 functions in inflammatory response evoked by protozoan parasites.

The Gasdermin Family

The gasdermins (GSDMs) are a family of recently identified intracellular proteins that elicit pyroptosis. The human genome encodes six paralogous members of GSDM family proteins: GSDMA, GSDMB, GSDMC, GSDMD, GSDME/DFNA5 and DFNB59 (also known as pejvakin) (40), and ten in mouse, including GSDMA1, GSDMA2, GSDMA3, GSDMC, GSDMC2, GSDMC3, GSDMC4, GSDMD, GSDME, DFNB59 (40, 41). The name gasdermin comes from the expression in the gastrointestinal tract and epithelium of the skin. All members of the GSDM family excluding DFNB59 are conserved and comprised of highly conserved NT and CT fragments that are separated by a central flexible and viable linker that harbour pore-forming activity (42). Upon cleavage by caspases or granzymes, the NT fragment of GSDMs binds to acidic phospholipids in the inner leaflet of cell membranes to form GSDM pores (42–45).

GSDMA

The human genome encodes a single GSDMA, whereas the mouse genome encodes three paralogs known as GSDMA1, GSDMA2 and GSDMA3 (46–48). Mouse GSDMA1 was the first cloned member of the GSDM family protein and was found exclusively in the upper gastrointestinal tract (46). Human GSDMA is expressed in skin and the gastrointestinal tract, including the epidermis, hair follicles, stomach and esophagus (40, 47, 49, 50) (Table 1), however, the protease that activates GSDMA has not been elucidated, though by conducting protein-protein network (STRING-db) (86) analysis, it predicts caspase-1 (red stippled circle) has a strong relationship with GSDMA (Figure 4A). Some evidence suggested that GSDMA may participate in TGF-β production of gastric epithelial cell apoptosis, and gain-of-function mutations in this protein have been discovered to result in hair loss and keratosis (47, 87, 88). Human GSDMA has three mice orthologs, and the generation of knockout (KO) mice displayed increased susceptibility to invasive infection (89) (Table 2). GSDMA genetic polymorphisms indicates a connection with inflammatory bowel disease (IBD) and asthma in children (103–106). However, the gain-of-function mutations were discovered to impair the interaction between the NT and CT fragments by interfering with autoinhibition, causing constitutive activation and inducing pyroptosis without unleashing autoinhibition (88) (Table 1). Similar to GSDMD-NT, when the NT fragments of GSDMA and GSDMA3 were overexpressed in HEK 293T cells, they enhanced pore formation in the cell plasma membrane and trigger pyroptosis-like features (42). Other studies have shown that the NT of mouse GSDMA3 associates with the chaperone protein, heat shock protein 90 (HSP90) (107), and STRING analysis reveals a potentially functional link between GSDMA and heat shock-related 70 kDa protein 2 (HSPA2) (Figure 4A). Though there are no studies to date depicting a connection between GSDMA and protozoan parasites (Table 1), recent studies conducted on group A Streptococcus pyogenes (GAS) revealed that the GAS cysteine protease SpeB cleaves GSDMA to trigger pyroptosis in keratinocytes (52, 89). Upon SpeB cleavage, GSDMA unleashes its NT that forms pores in the plasma membrane which act as a conduit to release intracellular products simultaneously allowing extracellular SpeB to diffuse into the cell, resulting in more GSDMA cleavage and IL-1β processing. Notably, SpeB processes IL-1β at a different site compared to caspase-1, indicating a caspase-1 independent pathway to release IL-1β. In addition, mouse deficient in Gsdma1 gene displayed blunt immune response to GAS, causing disseminated bacterial infection (52). It would be intriguing to determine if protozoan parasites could trigger the cleavage of GSDMA by activating proteases, and what are the consequences of forming GSDMA pores.

Figure 4

GSDMB

At present, GSDMB remains the least studied. GSDMB is the most divergent member among the GSDM family dominantly located in airway epithelium, oesophagus, stomach, liver, small intestine and colon (108, 109). Human GSDMB have at least four isoforms with viable linkers that are cleaved by granzyme A from cytotoxic lymphocytes to induce target cell pyroptosis (55, 110). However, Gsdmb has not been found in rodents and this limits the development of experimental tools to study GSDMB in mouse models (Table 2). The granzyme A-GSDMB pyroptotic axis may also play important roles in immunity to cancers in addition to microbial infections (Table 1), however, no predicted interactions were found between them (Figure 4B). Genome-wide association studies (GWAS) uncovered a strong correlation between GSDMB and susceptibility to inflammatory diseases including Crohn’s disease, asthma, and type I diabetes (111–113). However, the direct relationship between GSDMB and these inflammatory diseases need to be further identified. A single nucleotide polymorphism (SNP) was discovered to associate with upregulated GSDMB expression and increased susceptibility in asthma (56). GSDMB is frequently expressed in cancer cells, consequently, significant correlations were indicated between expression levels of GSDMB and overall survival of patients with bladder carcinoma or skin cutaneous melanoma (55). More recently, a study showed that upregulated of GSDMB in IECs was associated with increased susceptibility of IBD (57) (Table 1). An essential physiological restoration and recovery mechanism to maintain intestinal homeostasis is the resolution of inflammation, and IECs play a major role to undergo proper tissue restitution and repair (114). Specifically, GSDMB was found to be significantly upregulated in IECs from active IBD patients as compared to healthy individuals, suggesting a strong correlation between GSDMB in IECs and IBD progressions (57) (Table 1). Unlike other GSDM members, GSDMB can bind to cell membrane even with the full-length protein (113). Another unique feature about GSDMB is its NT was found to directly interact with caspase-4 CARD protein which may have the capability to upregulate the cleavage of GSDMD mediated by caspase-4 (61). This study discovered that a reduction of GSDMB expression alleviated GSDMD cleavage and programmed pyroptotic cell death (61). GSDMB overexpression facilitated GSDMD cleavage along with elevated lactate dehydrogenase (LDH) release (61), indicating that GSDMB could act as a regulator for GSDMD cleavage in certain circumstances including protozoan parasite infection. In addition, since GSDMB can promote caspase-4 activity by directly binding to the CARD domain of caspase-4, this suggests that GSDMB can play a role in Eh pathogenesis as caspase-4 regulates GSDMD pore-forming activity in response to Eh (22).

GSDMC

GSDMC, also known as melanoma-derived leucine zipper containing extranuclear factor, was named by its initial observation in melanoma metastases in mice (66). The expression of GSDMC is restricted to the esophagus, skin, spleen and vagina (109) (Table 1) and its expression was first used as a marker for melanoma progression (66). Upregulation of GSDMC was detected in human colorectal cancer tissues and was experimentally confirmed with its oncogenic potential (115). Human GSDMC is preferentially expressed in metastatic melanoma cells (66). Mice lack GSDMB but express GSDMC1, 2, 3, 4 (19) (Table 2). Knockdown of mGSDMC1-4 in B16 mouse melanoma was an accidental finding when dimethyl-α-ketoglutarate (DM-αKG) was used to treat HeLa cervical carcinoma cells (Table 2). The treatment of DM-αKG vastly triggered cell death, which presented with distinct morphology alterations in pyroptosis (91). Studies in Chinese Han population revealed that genetic polymorphisms of Gsdmc can alleviate the risk of Lumbar disc herniation, which is a common spinal disease (116). Like other GSDM family proteins, overexpressed GSDMC-NT can drive pore formation and cell pyroptosis in 293T cells (42). To date, no protease has been identified to initiate GSDMC cleavage (66) (Table 1). Based on STRING analysis (86), GSDMC interacts with LRRC57 (Figure 4C), and Synaptosome Associated Protein (SNAP23) was identified as the downstream of LRRC57 in human (117), indicating an interesting relationship between GSDMC and SNAP23. SNAP23 was found to be downregulated in Eh-induced hyperactivated macrophages (22), which may play a major role in repairing GSDMs pores on the plasma membrane. Delineating the interactions between GSDMC and SNAP23 could strengthen our understanding on the balance between cell hyperactivation and cell pyroptosis, and what triggers GSDMs to switch from a pyroptotic role to a non-pyroptotic dominant function. It was recently shown that GSDMC is specifically cleaved by caspase-8 following tumor necrosis factor α (TNF-α) stimulation under hypoxic conditions (65). TNF-α-induced GSDMC cleavage at Asp365, unleashing the GSDMC-NT to form pores and initiate cell pyroptosis in breast cancer cells (65). In Eh-stimulated macrophages, we detected bioactive IL-1β release in CRISPR-Cas9 gene edited GSDMD KO cells, suggesting that perhaps other GSDM pores (22) including GSDMC may have occurred to elicit robust pro-inflammatory responses.

GSDMD

GSDMD is found in the gastrointestinal tract and in sentinel cells of the immune system, macrophages and dendritic cells (118). It was the first GSDM protein identified as the executor of pyroptosis that acts downstream of inflammatory caspases (19, 20). Gsdmd^-/- mice has been widely used in research including inflammatory-caspase-associated autoinflammatory conditions and septic shock, and display protection from death as compared to wild-type counterparts (Table 2). By investigating polymorphisms in GSDMD, it was found that polymorphisms can dramatically impact GSDMD functions by affecting sites that are considered as structurally important (119). A prominent portion of GSDMD research has been focused on bacterial exposure, whereas in vitro studies in human and mouse macrophages discovered that Eh activates caspase-4 via noncanonical inflammasome pathway to regulate the cleavage of GSDMD to mediate IL-1β secretion (21), and STRING analysis (86) indicates strong interaction between GSDMD and caspase-4 (Figure 4D). GSDMD is the most well-characterized GSDM protein with its pore-forming NT effector that punches pores in plasma membrane. This discovery has shifted the paradigm of our understanding on how programmed cell death occurs (19). Remarkably, the effector molecule that induced pyroptotic cell death remained unknown until 2015 when GSDMD was discovered as the key effector of pyroptotic cell death and a cleavage target for caspase-1 and -11 (19, 20) (Figure 4D). The gene Gsdmd encodes the 480-residue protein GSDMD, which contains an NT and a CT domain (20, 120). Mechanistic studies demonstrated that GSDM-NT harbours the intrinsic pore-forming and pyroptosis-inducing activity (19, 20, 42). GSDMD are expressed as inactive forms in the resting state, where the CT fragment is held back in check with the NT component to trigger an intramolecular auto-inhibition to inhibit GSDMD cleavage (42, 121). Upon activation by cytosolic danger and infection sensors in macrophages and dendritic cells cleave GSDMD within the linker region, liberating the active NT pore-forming domain to assemble GSDMD pores in the cell membrane (19) (Figure 5). Recently, it was reported that GSDMD-CT not only auto-inhibits GSDMD-NT, but also provides a platform for recruiting inflammatory caspases and GSDMD activation (122). Thus, it is not surprising that mutations within the GSDM-CT region can impair the inhibitory interaction between the CT and NT domains that can trigger spontaneous cleavage of GSDMs. GSDM pores induce disruption in cell membrane integrity that ultimately leads to plasma membrane rupture and osmotic cell lysis, in which pro-inflammatory cytokines are released into the extracellular space (118, 123, 124) (Figure 5). Expression of GSDMD-NT itself can trigger inflammatory cell death, whereas overexpression of GSDMD-CT can inhibit pyroptosis (19). Immune cells release pro-inflammatory molecules into the extracellular space, therefore eliciting inflammatory and immune responses that play a role in innate host responses to parasitic infections. Eh as an extracellular protozoan parasite that induces outside-in signaling in human macrophages to activate caspase-4 similar to Eh-induced caspase-1 activation (22). Importantly, we recently shown that caspase-4 triggered GSDMD cleavage was more efficient in the release of IL-1β independent of the canonical NLRP3 inflammasome pathway while keeping the cells alive (22) (Table 1, see section below on intracellular protozoan parasites). By functional enrichment analysis on protein-protein interaction networks (86), GSDMD is intensively connected with both caspase-4/1 and NLRP3/1 inflammasomes. Humans with mutations in NLRC4 develops an autoinflammatory syndrome presented with acute fever and feature indicative of Macrophage Activation Syndrome (MAS). MAS patients present with elevated serum IL-18 as predicted by STRING analysis (Figure 4D).

Figure 5

A mounting body of evidence has demonstrated that neutrophils are crucial effector cells against Eh and some intracellular protozoan parasites (125–128) (Table 1). Inflammasome activation promotes neutrophil recruitment, which is critical to parasite dissemination and/or exacerbation of disease (129). In contrast to macrophages, GSDMD cleavage in neutrophils is caspase-independent, and is mediated by a neutrophil-specific serine protease, elastase (ELANE) released from cytoplasmic granules into the cytosol during neutrophil death (92). ELANE cleaves GSDMD to perforate the plasma membrane to trigger pyroptosis in neutrophils. GSDMD in neutrophils are linked to azurophilic granules and upon cleavage into GSDMD-NT, it transports to azurophilic granules that results in leakage of ELANE into the cytosol to cleave GSDMD, leading to a secondary cleavage on GSDMD (130). Neutrophil extracellular traps (NETs) catch and damage Eh and play an important role in innate host defense against infection (131). These findings highlight the principal differences between neutrophil and macrophage in GSDMD regulation that implicate neutrophil-specific functions in response to parasites (130).

GSDME (DFNA5)

GSDME is variably expressed in a range of human cells and tissues, including the brain, endometrium, placenta and intestine (132) and was characterized as the causative gene for nonsyndromic hearing loss and as a tumor suppressor (40, 133) (Table 1). GSDME deletion by CRISPR/Cas9 gene editing in various cell types has been generated, for example, murine melanoma cell line B16 and thymoma cell lone EG7-Ova (99) (Table 2). Gsdme^-/- mice exhibit healthier and more robust phenotypes after peritoneal injection of cisplatin comparing to wild-type mice (74) (Table 2). Other studies have reported gain-of-function in Gsdme leads to disruption of exon 8 at mRNA level and cause nonsyndromic DFNA5 hearing impairment (77–79, 134–137). It is not clear what the physiological role of GSDME is in these tissues and cells, where inflammation might be harmful (96). GSDME and pejvakin (PJVK) belong to the deafness-associated genes (DFN) and their protein sequences cluster together, distant from the other GSDMs (GSDMA-D). Evolutionarily, GSDME and PJVK are among the oldest GSDM members to date, with resemble sequences found in lower vertebrates and some invertebrates (138, 139). DFNA5 plays a role in the TP-53-regulated cellular response to DNA damage probably by cooperating with TP53 (140). Notably, GSDME was recently shown to be cleaved and activated by caspase-3 with a role in anti-tumor immunity (141, 142) (Table 1), driving chemotherapy drug-induced normal-tissue damage or viral infection-mediated secondary necrosis (74, 75) as confirmed by STRING analysis (86) (Figure 4E, Table 1). A recent study revealed that NLRP3 inflammasome activation causes delayed necrotic cell death by recruiting ASC in caspase-1/11 deficient macrophages (143). Additionally, ASC triggered caspase-8 activation to process GSDME, which is essential for caspase-1 independent necrosis without detectable IL-1β secretion, suggesting an alternative pathway for necrotic cell death regulated by NLRP3 inflammasome upon inhibition on caspase-1 (143). Furthermore, constitutive NLRP3 activation retains the capability to trigger inflammation in mice lacking GSDMD likely following GSDME-regulated pyroptosis (144). Thus, GSDME presents as a potential treatment for inflammatory disorders induced by sustained inflammasome activation (Table 1).

DFNB59

DFNB59 or PJVK is a protein related to hearing impairment or loss in humans and mice (85, 145, 146). Since all GSDM family members share the two-domain structure, excluding DFNB59, it is a more remotely associated GSDM family member with a truncated non-homologous CT fragment (147) with no interaction with other GSDM family members (Figure 4F). DFNB59 mRNA is present in the brain, eyes, ears, heart, liver and intestines (85, 148) (Table 1). Even though GSDME and DFNB59 are associated with nonsyndromic hearing loss and impairment, Dfnb59^-/- but not Gsdme^-/- mice display hearing dysfunction (85, 100–102) (Table 2). Using Pjvk KO alleles, it was shown that PJVK was essential for regular mechanotransduction in hair cells (149). Missense mutations within the NT of DFNB59 results in impairment of transmitting the auditory signal through auditory neurons (Table 1), present either dysfunctional in cochlear outer hair cells (100) or auditory neuropathy (85). It is still not known if DFNB59 is a pore-forming protein or if it remains physiologically active under homeostasis, since the NT of DFNB59 is extremely short and might fail to trigger autoinhibition.

Gasdermin D-Mediated Cell Pyroptosis

Pyroptosis (in Greek, pyro means fire and ptosis means falling) is a lytic form of regulated cell death that is induced by inflammatory caspase-1, 4, 5, and 11 (mouse) (150, 151), and was first reported as a cell biological phenomenon in macrophages during Shigella flexneri and Salmonella enterica serovar Typhimurium infections, respectively (152–154). GSDMD pores in the plasma membrane act as conduits through which low molecular weight cellular contents are released into the extracellular space to elicit inflammation. However, once the volume exceeds membrane capacity, a membrane rupture event occurs to release soluble cytosolic contents (19). This tear is robust enough to instantly dissipate soluble protein like LDH, while organelles are retained (155). During cell pyroptosis, the damaged membrane forms large ballooning bubbles and dying cells begin to flatten as their cytoplasmic contents are released (156). The rapidity of cell death and morphological alterations are signatures to distinguish pyroptosis and apoptosis (118). It is predicted that after the rupture event, the osmotic pressure achieves a new balance, and stops further volume increases (157). Once the pore-forming fragment is unleashed from the CT repressor domain, it subsequently oligomerizes to form the pyroptotic pores, in which an estimated 16 pore-forming fragment (NT) monomers oligomerize to form pores with a diameter of approximately 10-15 nm of range (42, 43, 45), or around 21 nm (44). These pores mediate the passage of cytokines and diverse cytoplasmic contents and undermine the cellular ionic gradients (Figure 5). The opening of GSDMD pore breaks the normal permeability barrier of the plasma membrane, resulting in membrane disruption, which causes an increase in osmotic pressure causing an influx of water, leading to the cell volume to increase (157). As a consequence, this drives cell swelling and plasma membrane rupture, which eventually lead to cell pyroptosis (Figure 5).

NINJ1 Actively Mediates Plasma Membrane Rupture During Lytic Programmed Cell Death

It was originally thought that plasma rupture occurred after pore formation as a passive cellular event triggered by shear force (158). However, recent studies have shown that plasma membrane rupture is an actively regulated process that is mediated by a specific membrane protein, ninjurin-1 (NINJ1) (23). Deletion of NINJ1 in bone marrow-derived macrophages (BMDMs), inhibited the release of HMGB1, a pro-inflammatory DAMP (159), despite exhibiting normal GSDMD-dependent release of IL-1β, indicating that the rupture of plasma membrane was an abnormal event. Macrophage’s deficiency in NINJ1 displayed significant decreased in LDH release in the absence of GSDMD cleavage (23). IL-1β secretion was unaffected in NINJ1^-/- BMDMs, supporting the notion that IL-1β is predominantly secreted through GSDMD pores.

NINJ1 is a 16 kDa cell-surface protein that contains two transmembrane regions with N and C termini exposing to the cytoplasm (Figure 2). With the use of artificial dyes of various sizes, it was revealed that NINJ1 acted downstream of GSDMD pores, and overexpressing NINJ1 in HEK 293T cells enhanced cytotoxicity (160). This finding was paradigm-shifting, as membrane rupture event has been long presumed to passively and spontaneously occur after cell death is triggered. Though much work needs to be done on the interaction between GSDMD and NINJ1, there are many unanswered questions: what drives the oligomerization to induce NINJ1 activation; what role does GSDMD play in regulating NINJ1 activity; what are the functions of the other NINJ family members and do they interact with each other and what is the biochemical activity of the NINJ family. More importantly, the link between NINJ1 activity in plasma membrane rupture and cytotoxicity requires more attention.

In terms of therapy, it is promising to target GSDMD or NINJ1 to limit inflammation rather than to simply block either NLRP3 or IL-1β, because the ultimate goal is to prevent pyroptosis in diseases such as autoinflammatory genetic disorders (97). In addition to this, a group of small molecules that target and inhibit GSDMD has been reported (161, 162). Because robust evidence indicates that NINJ1 as another new therapeutic target to limit inflammation. This could be achieved by either knocking out NINJ1 or with an antagonistic anti-NINJ1 antibody, aimed at inhibiting NINJ1 to reduce inflammation and suppression of plasma membrane rupture (23).

The GSDME/Caspase-3 Signaling Function as a Switch Between Apoptosis and Pyroptosis Against E. histolytica and Other Parasitic Infections

Apoptosis constitutes a programmed non-lytic and non-inflammatory mode of cell death involving apoptotic executioner caspase-3, caspase-6 and caspase-7. Cell membrane integrity is preserved at early stages of apoptosis, and apoptotic cells are efficiently eradicated from healthy tissues by phagocytosis prior to being lysed. Classical apoptosis is a physiological programmed cell suicide in which cells undergo characteristic morphological changes, including membrane blebbing, cell shrinkage, DNA fragmentation, chromatin condensation (141, 142), whereas pyroptotic cells rapidly lose cell membrane integrity, increase in size, and have smaller nuclei by forming GSDM pores in which the damaged membrane forms large ballooning bubbles, which are of distinct morphological changes as apoptosis (156, 163–165) (Figure 6A). It is a well-defined step-wise process for Eh to kiss host cells to death via Gal-lectin contact with upregulation of intracellular Ca²⁺ levels followed by dephosphorylation of host proteins that activates caspase-3 to promote cell death (166). Blocking Ca²⁺ channels and/or Ca²⁺ chelators inhibit Eh killing of host cells (166, 167). Eh-induced apoptosis was found not to be dependent on caspase-8 or caspase-9 (168). Casp-3 KO mice are tolerant to amebiasis and a caspase-3 pharmacological inhibitor decreased Eh cytotoxicity (168, 169). Apoptosis is immunologically silent, thus by inducing apoptosis, Eh can dampen the inflammatory response to escape from being recognized.

Figure 6

Recent studies have significantly advanced our knowledge on the mechanisms and physiology roles of pyroptosis. Although pyroptosis and apoptosis have been considered as two distinct pathways, apoptotic stimuli can trigger pyroptosis under selective scenarios. GSDME is activated during classical apoptosis, following caspase-3 cleavage after Asp270 within the linker region (Table 1), which switches non-inflammatory apoptotic cell death into inflammatory pyroptotic death that express GSDME, alternatively, depletion of GSDME can switch apoptosis to pyroptosis in cells (74, 75). More specifically, activated caspase-3 can cleave GSDME to induce pyroptosis instead of apoptosis (74, 75). When GSDMs are activated by granzymes or caspases, it can also induce apoptosis in certain situations, where the expression of GSDMs is too low to induce pyroptosis, and vice versa, caspase and granzyme-induced apoptosis can be switched to pyroptosis by the expression of GSDMs (164). Another example is the discovery of the apoptotic initiator caspase-8 to interact with the adaptor protein ASC (170, 171). On the other hand, TNF receptor activation activates caspase-8 to induce GSDMD-dependent pyroptosis during pathogenic Yersinia infection (67, 68). Interestingly, activation of the inflammasomes drives the activation of apoptotic caspase-3/7 (172–175). Strikingly, deficiency of GSDMD remarkably postponed and decreased the amount of LPS-induced caspase-3 activation (75). The pore-forming fragment of GSDMD, but not full-length GSDMD, was discovered to cause cytochrome c release and caspase-3 activation (99), indicating that targeting at mitochondrial membrane, releasing cytochrome c and activating caspase-3 is a common mechanism employed by the gasdermin family members to potentiate apoptosis. At the onset of apoptosis, caspase-3 proteolytically cleaves GSDME, which is strongly implicated in tumor suppression (74). By inducing GSDME expression in vitro, it supresses colony formation and tumor cell proliferation in gastric cancer, melanoma and colorectal cancer and reduced metastasis in breast cancer (99, 176–178). Caspase-3 was shown to be involved in Jurkat T cell apoptosis induced by Eh through in vitro studies (168). Eh-induced apoptosis required contact via the Gal lectin but was independent of their cysteine proteases by applying the cell-permeable cysteine proteinase inhibitor, E64c. With the use of caspase-3 inhibitor Ac-DEVD-CHO, it was determined that caspase-3-like activity was necessary for Eh to trigger Jurkat cell apoptosis, since this inhibitor completely blocked Jurkat cell DNA fragmentation.

Transcriptomic analysis of mice brain that were infected with T. gondii compared to uninfected mice using RNA sequencing, showed that inflammasome-regulated pyroptosis was an important host cell death pathway to control infection (128, 179). By performing host-parasite interactome analysis, nine pyroptosis-related differentially expressed transcripts (DETs) were upregulated in infected mice, including casp-4, gsdmd and pycard, while gsdme was downregulated in chronic infection (180). Additionally, IL-1β and IL-18 were upregulated during chronic T. gondii infection, suggesting these inflammatory cytokines are crucial to assist mice to mount an appropriate inflammatory response to prevent latent T. gondii infection (180). During T. gondii infection, infected cells secrete growth factors to inhibit neutrophil apoptosis, by triggering Mcl-1 expression (181). Delayed neutrophil apoptosis may contribute to a robust pro-inflammatory response (181). Leishmania infection reduces caspase-3 activity and postpones spontaneous apoptosis in human neutrophils (182), serving as “trojan horses” to invade macrophages that are phagocytosing apoptotic cells (183). Clearly, more work needs to be done on how GSDM family members are involved as a master switch from apoptosis to pyroptosis, especially with protozoan parasite infections (Table 1).

Gasdermin D Serves as a Gatekeeper to Release IL-1β in Hyperactivated Macrophages in Response to E. histolytica

When Eh contacts macrophage via the Gal-lectin adhesin, surface EhCP-A5 RGD sequence binds α₅β₁ integrin that triggers Src family kinase phosphorylation and the opening of pannexin-1 channel. Pannexin-1 is a membrane channel for ATP that induces an extracellular burst of ATP, which engages the P2X₇ receptor in an autocrine or paracrine fashion to activate the NLRP3 inflammasome and caspase-1 resulting in cell pyroptosis (184). By inducing the outside-in signaling in macrophage, Eh activates caspase-4 via the noncanonical inflammasome pathway to initiate IL-1β secretion similar to caspase-1 by keeping the cells intact (Figure 2) (22). The mechanism of human caspase-4 activation requires live Eh in direct contact with macrophage to trigger outside-in signaling in macrophage to induce the generation of reactive oxygen species (ROS) and K⁺ efflux (21). Activation of pro-caspases undergoes dimerization or oligomerization with a succeeding cleavage into a small subunit and a large subunit. Upon being activated, it cleaves GSDMD to release the NT pore-forming domain that promotes pore formation to cause Na⁺ influx, cell swelling that ultimately triggers rupture in the plasma membrane. In response to Eh stimulation, caspase-4 also interacts with caspase-1 in a protein complex that potentiate the cleavage of caspase-1 CARD domains to enhance IL-1β secretion (21). More recently (22), we showed that Eh-induced IL-1β release was not due to massive cell pyroptosis, but rather induce macrophages to reach a stage of “hyperactivation” that caused sustained release of pro-inflammatory cytokines, revealing a significant non-pyroptotic role for GSDMD. This is in marked contrast to nigericin stimulated LPS-primed macrophages that activated caspase-1, resulting in massive cell pyroptosis (22). Mechanistically, Eh triggered caspase-4 activation, GSDMD cleavage and pore formation within 5 min and with IL-1β secretion as early as 30 min in the absence of cell death (22). An important finding was that caspase-4 cleavd GSDMD at the identical amino acid as caspase-1 to maximally regulate IL-1β secretion in response to Eh. Eh-induced IL-1β secretion was independent of pyroptosis as revealed by pharmacologically inhibiting GSDMD pore formation and in CRISPR-Cas9 gene edited GSDMD KO macrophages (22). We theorize that Eh-induced caspase-4/1 activation induced fewer GSDMD pores than NLRP3 inflammasome agonist such as LPS + Nigericin. If fewer GSDMD pores are generated, the cell might respond by initiating compensatory mechanisms to downregulate cell volume allowing for sustained IL-1β secretion while maintaining cell viability, and this may be a unique mechanism in the biology of Eh that could play a crucial role in disease pathogenesis and host defence.

It is controversial whether IL-1β is effectively released via pyroptotic membrane rupture or in the absence of pyroptosis (185–189). With intracellular pathogens, pyroptosis mediated by GSDMD was necessary for IL-1β release from macrophages exposed to inflammasome activators (155). Cell- and liposome-based assays demonstrated that GSDMD pores were required for IL-1β transport across an intact lipid bilayer (42–45). Of note, GSDMD^-/- macrophages are still able to release caspase-1-processed bioactive IL-1β via PIP2-mediated plasma membrane binding that is of a much slower rate than GSDMD-dependent release (190). These findings identify a non-pyroptotic function for GSDMD, and raised the possibility that GSDMD pores represent conduits for the secretion of cytosolic cytokines under conditions of cell hyperactivation (191, 192).

Gasdermin D-Regulated Cell Hyperactivation

How can a cell release IL-1β/IL-18 through GSDM pores in the absence of cell lysis? Secretion of the IL-1 family of cytokines was widely considered a caspase triggered pyroptosis-dependent event, as IL-1β and IL-18 lack a protein secretion signal sequence (193). Recently, the concept of “unconventional protein secretion” was advanced to describe GSDMs pore-mediated pro-inflammatory cytokine release (194, 195) and cellular alarmins such as ATP and high-mobility group box 1 (HMGB1) at the same time to augment inflammation in tissues to recruit immune cells against infection and damage. Phagocytes can achieve a state of hyperactivation, which is defined by their ability to secrete the IL-1 family of cytokines while retaining viability, but it remains unclear how IL-1β can be secreted from living cells (196).

When macrophages, dendritic cells and neutrophils survive inflammasome-mediated GSDMD pore-forming activity without membrane rupture and pyroptosis, they retain their ability to produce pro-inflammatory cytokines, termed “hyperactivated” cells (197). The hyperactivated cells and pyroptotic cells can be distinguished by measuring LDH in cell supernatants, which are too large to be secreted through GSDMD-NT pores and are only released upon cell lysis (Figure 6A). Mature IL-1 family cytokines and alarmin molecule HMGB1 are small proteins that are readily released through these pores. Alternatively, if the number of GSDMD pores patched in cell membrane exceeds the recovery capability of the cell, cell volume in turn increases. Once the volume exceeds membrane capacity, the plasma membrane divides from the cytoskeleton in large fluid-filled balloons. These pores disintegrate the cell membrane and are large enough to rapidly lose soluble proteins including LDH, whereas, organelles are retained (155). Shortly after the formation of GSDMD pores, a pyroptosis-associated membrane-rupture event proceeds which releases soluble cytosolic contents. Pyroptotic cells release both LDH and cytokines (196) (Figure 6A). Hyperactivated cells can process and pump out more inflammatory components as compared to their pyroptotic counterparts (141) (Figure 6B). At present, it still remains unclear what determines whether cleaved GSDMD causes pyroptosis or hyperactivation. Recently, researchers have proposed a possible mechanism of cell membrane repair response at the site of lesion, which efficiently recover membrane integrity, allowing cell survival. The battle between how promptly and efficiently the membrane repair response is initiated and how robust and fast the damaged is caused, is presumably dependent on how much and how efficiently GSDMD is cleaved.

Mechanisms of Pyroptotic Membrane Repair Regulation

Cells that have GSDM pores on plasma membrane can be sensed by an instantaneous increase in intracellular Ca²⁺ to trigger membrane repair by recruiting the endosomal sorting complexes required for transport (ESCRT) machinery to disrupted membrane areas and repair them in ectosomes (198) (Figure 7). Mammalian cells can repair plasma membrane damages when size of the disruption is not large (<100 nm) by a variety of mechanisms (199). Cell membrane that are damaged by GSDM pores likely induce activation of the ubiquitous plasma membrane damage repair response in eukaryotic cells, restoring membrane integrity rapidly to increase cell survival (200). The two major well-defined mechanisms are: Acidic Sphingomyelinase (ASM)-dependent endocytosis of plasma membrane pores and ESCRT-mediated shedding of injured plasma membrane (Figure 7). The ESCRT machinery was initially found in yeast, where it was identified to regulate protein trafficking and intraluminal vesicle formation at the distal side of cell membrane (201). The ESCRT machinery is a multiprotein complex contained a group of subcomplexes, including ESCRT 0, I, II, III, and ESCRT-III was discovered to be essential in membrane repair process (202, 203). The pyroptosis membrane repair involves massive endocytosis of damaged membrane, mostly from lysosomes (204) and exocytosis by promoting lipid raft formation (205, 206) (Figure 7). We have shown that when EhCP-A5 engages α_vβ₃ integrin on goblet cells, it facilitated outside-in signaling cascade by activating SRC family kinase, resulting in the activation of several kinases including PI3K and PKC (18). The trafficking vesicle marker, myristolated alanine-rich C-kinase substrate (MARCKS), was the target for PKC and has been implicated in docking vesicles for SNARE-mediated membrane fusion. We discovered that the R-SNARE vesicle-associated membrane proteins 8 (VAMP8) expressed on mucin vesicles was critical for SNARE-mediated exocytosis of mucin secretion in response to Eh (18). Thus, SNARE complex in goblet cells regulates mucin exocytosis and degradation of these regulatory pathways aggravates Eh pathogenesis (18). After the membrane is damaged and the uncontrolled entry of Ca²⁺ occurs, lysosomes are recruited to the site of the lesion and subsequently fuse to the plasma membrane, releasing ASM that hydrolyzes sphingomyelin into ceramide. This in turn, facilitates endosomes formation that internalize the lesion and repair membrane integrity (206–209) (Figure 7). A group evaluated the involvement of ASM in the repairing plasma membrane that caused by Eh. They found that damage to Eh membrane promotes lysosomes migration to the site of impairment where lysosomal ASM is released, forming membrane patches and endosomes to incorporate the lesion area and repair cell membrane, thus this mechanism facilitates amoebic viability (210).

Figure 7

Ca²⁺ influx through GSDMD pores acts as a signal for cells to undergo membrane repair by recruiting the ESCRT machinery to the site of damage or ruptured membrane (198) (Figure 7). Inhibiting the ESCRT-III assembly robustly favors pyroptosis in mouse BMDMs (198), suggesting a crucial anti-inflammatory role for the ESCRT-III machinery to restore cell homeostasis after GSDMD pore formation (Figure 7). Imaging the disruption of the electrochemical gradient using the Ca²⁺ dye Fluo-8, and loss of membrane integrity using propidium iodide (PI) in mouse BMDMs, showed that the ESCRT system dampens GSDMD pore-forming activity and downregulated cell death and IL-1β secretion by acting downstream of caspase activation and GSDMD oligomerization (198). However, it remains vague whether ESCRTs could serve as a control of caspase activation to regulate GSDMD activity, and if other GSDMs are involved in the process. ESCRT-III was discovered to repair mixed lineage kinase domain-like protein (MLKL)-induced plasma membrane injury in the process of necroptosis, indicating this membrane repair process can increase cell viability (triggering hyperactivation instead of pyroptosis) to combat the pore-forming activity of GSDMD (198) (Figure 7). The mechanisms on if bioactive IL-1β is packaged into micro-vesicles to be released or they are secreted primarily from the GSDMD pores remain to be elucidated. It is still unclear if these membrane repair processes occur in cells with GSDMD-disrupted plasma membranes.

Gasdermin Pores Target Mitochondrial Membrane to Eradicate E. histolytica and Other Protozoan Parasites

GSDM-NT can bind and insert into internal cellular membranes (70, 99, 107, 130), including mitochondria and bacteria to kill the cells (43). However, bacteria are known to survive during pyroptosis (155, 211) so the physiological relevance of bacterial membrane-targeting remains unclear. The NT of GSDMD and GSDME when translocated to mitochondria, permeabilize the outer membrane and destroy their function, resulting in the production of ROS (Figure 2, Figure 6 and Figure 8), loss of mitochondrial membrane potential and the release of cytochrome c, which subsequently activates caspase-3 to augment cell death (99). For example, bacteria that remain viable during pyroptosis but are damaged may drive by the formation of GSDMD pores (43) and ROS (212). ROS and the release of mitochondrial DNA, mitochondria, nuclei, and ASC specks via cell membrane rupture and Ca²⁺ influx and K⁺ efflux through GSDM pores can trigger activation of inflammasomes (213). Noncanonical signaling pathway primarily triggers GSDMD cleavage and induces pyroptosis, however, activation of noncanonical signaling pathway can trigger assembly of the canonical NLRP3 inflammasome, possibly via the generation of mitochondrial ROS and K⁺ efflux, implicating a certain degree of crosstalk between these two pathways (214–216) (Figure 2). The noncanonical caspase-4 activation in response to Eh involves K⁺ efflux and ROS generation that can play an important role not only in amplifying downstream pro-inflammatory responses (Figure 2), but by interacting with the canonical NLRP3 inflammasome pathway to enhance the cleavage of caspase-1 CARD proteins (21). K⁺ channels are the most common identified ion transporter, and their critical roles was determined from colon biopsies from human with amebiasis with the demonstration of restrained K⁺ channel expression. Blocking K⁺ channels with genetic silencing or pharmacologic inhibitors suppressed caspase-1 activation, IL-1β secretion and cell pyroptosis in macrophages (217). The production of ROS is dispensable in killing Leishmania amazonensis but plays a major role in regulating inflammatory responses by regulating neutrophil infiltration into lesions (218). Activated phagocytes elicit cytotoxic impacts through ROS generation to kill pathogens by oxidative damage in Chagas disease causing Trypanosoma cruzi (219–223).

Figure 8

Pyroptosis Defends Against Intracellular Protozoan Parasites

Intracellular protozoan parasites reside in neutrophils, dendritic cells and macrophages. GSDMD-mediated pyroptosis can effectively damage intracellular parasites-residing niche, releasing cytosolic contents to promote pathogen expulsion. This in turn, triggers a strong inflammatory response to eliminate the compromised cell. Removing the intracellular replicative niche is beneficial to the host, however, it raises the interesting question, how does pyroptotic cells or infected macrophages ultimately eradicate pathogens?

Trypanosoma cruzi

Trypanosoma cruzi is an intracellular protozoan parasite that causes Chagas disease, which manifests as fever, fatigue, and headaches during early stage of infection, with potential to progress to heart failure and severe gastrointestinal complications (224–226). During the acute phase of infection, T. cruzi in circulating blood results in fever and swelling around the site of infection (227). Innate and adaptive host immune responses are both indispensable to control T. cruzi infection (228, 229). Upon lysing the vacuolar membrane, T. cruzi gains access to the host cell cytoplasm, where it undergoes replication (Figure 8A). Innate immune sensing by the NLRP3 inflammasome critically contribute to eliminating T. cruzi from healthy tissue (230, 231) (Table 3). NLRP3^-/-, caspase-1^-/- and Asc^-/- mice display more severe parasitemia (231) and lower survival probability (230) compared to wild-type mice. Cathepsin B is essential for NLRP3 activation in response to T. cruzi, and pharmacologically inhibiting cathepsin B abolishes IL-1β release (231) (Figure 8A). Interestingly, NLRP3 deficient macrophages are not only presented with impaired IL-1β secretion but also nitric oxide (NO) release that causes increase in parasite replication (231). NO produced by innate immune cells is trypanocidal to control T. cruzi replication (246). Macrophages serve as first responders by activation of NAD(P)H oxidase (NOX2) and ROS production to eliminate T. cruzi (247) (Figure 8A). NOX2 and ROS promote T cell-mediated adaptive immune response and deficiency in them causes defective splenic activation of cytotoxic T cell immunity against T. cruzi invasion (248). By infecting p47^phox-/- macrophages with T. cruzi in vitro, NOX2 and ROS were discovered to regulate cytokinopathy through controlling cytokine gene expression. Cytokinopathy was demonstrated as a molecular mechanism in cardiomyopathy in Chagas’ disease by cardiac gene expression profiling (249). Under situations like trauma, infection, and inflammation, macrophages become activated and secret robust level of inflammatory cytokines including IL-1 and IL-6, triggering the cascade that results in cytokinopathy (250). However, with deficiency of NOX2, CD8⁺T cell generation and activation were compromised, causing parasite burden, tissue damage and death (248).

GSDMD pore formation from NLRP3 inflammasome activation induces autophagy and may serve as a valuable anti-parasitic mechanism to eliminate T. cruzi from the host (251) (Table 1 and Figure 8A). By studying the interplay between inflammasome and autophagy in T. cruzi-infected mice and peritoneal macrophages, it was demonstrated that autophagy governs trypomastigotes outcome and activity at early stages of invasion by forming the NLRP3-dependent autolysosomes (252). NLRP3 inflammasome is also a requirement for triggering functional autophagy in T. cruzi activated macrophages (252) (Table 3). Autophagy and autophagy associated proteins not only regulate excessive inflammatory responses (232) but also target intracellular pathogens and organelles (253). Thus, deficits in autophagy molecules can result in uncontrolled inflammasome activation and subsequent immunopathology (254, 255). Autophagy disrupts pyroptosis by downregulating GSDMD cleavage (256) (Table 3). A recent study revealed that inhibition of mammalian target of rapamycin (mTOR) signaling upregulated NLRP3 expression, ROS generation and IL-1β release that boosted the efficiency of parasite control in macrophages (257) (Table 3); however, the direct effect and connection between autophagy and rapamycin treatment are unknown (257). Another study reported that rapamycin as an autophagy agonist, prevents GSDMD-mediated pyroptosis after LPS treatment (258). Autophagy was demonstrated to coordinate GSDME-induced pyroptosis by utilizing chloroquine to block autophagy pathway in human melanoma cells following an unclear mechanism (233). It will be of interest to uncover the interplay between autophagy and GSDMD/GSDME to shed light on the role of GSDMs in T. cruzi infection (Table 3).

Plasmodium

Malaria is a parasitic disease caused by the protozoa pathogens of the Plasmodium genus, which accounts for 228 million infected people globally in 2018 (259). Transmission occurs primarily through the bite of an infected female Anopheles mosquitoes, which inoculate the highly infective sporozoite forms into the mammalian host (260, 261). Different species can result in various clinical outcomes. This parasite has a unique life cycle in which sporozoites enter circulation and liver, where they undergo replication and differentiation (262). Upon exiting infected hepatocytes, red blood cells (RBCs) are infected where the parasites transform into trophozoites (263). Excessive activation of inflammatory responses in malaria causes a pro-inflammatory cytokine storm that coincides with severe fever episodes in patients that can be detrimental to the host. The cytokine storm contains IL-1β, TNF-α and IL-12 (262, 264), which effectively can control parasite replication (262). The release of inflammatory effectors is the consequence of hemozoin (265) (Figure 8B). The majority of the liver damage in malaria is an outcome of high oxidative stress accumulated by heme and infiltrated neutrophils regulated by NF-κB (266). When Plasmodium digests hemoglobin it converts free heme into an insoluble crystalline manner named hemozoin. Hemozoin drives inflammation in both sterile and infectious conditions, contributing to the pathogenesis of hemolytic disorders, including sickle cell disease and malaria (267, 268). Since the generation of hemozoin is a critical step for Plasmodium survival, it becomes a promising target for antimalarial drug development (269).

In the parasite vacuole, some Plasmodium-derived specific molecules, including hemozoin-derived from RBCs, parasite double-stranded DNA (dsDNA) and cathepsin are released in the cytoplasm to trigger NLRP3 inflammasome activation (234, 235) (Figure 8B). Sufficient NLRP3 inflammasome activation requires K⁺ efflux and NADPH oxidase induced by hemozoin in P. berghei ANKA sporozoites, suggesting NLRP3 as an essential player in cerebral malaria in mice, while not controlling parasitemia (270). By dissecting the mechanism of hemolysis, it was found that hemozoin triggered NLRP3 inflammasome activation in LPS-primed macrophages to promote IL-1β release (271). In addition, hemozoin-induced sterile hemolysis was demonstrated to trigger ROS production, tyrosine kinase (Syk) and NADPH oxidase activation that was crucial to inflammasome assembly (271). It is not known if this mechanism is involved in malaria pathogenesis. Conversely, NLRP3 was found to have a toxic impact in malaria, as mice deficiency in inflammasome components had higher survival rate with a lethal dose of P. chabaudi (234).

Caspase-8 was reported to be a primary mediator of systemic inflammatory response in P. chabaudi infected mice and in P. berghei experimental cerebral malaria. Knockout of caspase-8/1/11 or caspase-8/GSDMD resulted in disruption of TNF-α and IL-1β production, uncovering a supplementary and indispensable role for caspase-8 and GSDMD in malaria pathogenesis (236). The role of caspase-8 on IL-1β release needs more investigation as it is was shown to be involved in the cleavage of GSDMD (67). However, none of these roles in malaria pathogenesis has been addressed to date. It is not known whether these cytokines are secreted through GSDMD pores or it is a pyroptosis-dependent event or if other GSDMs might be involved (Figure 8B). A more comprehensive understanding using different Plasmodium species and in different models of disease would be beneficial to dissect the mechanisms on progression and regulation of malaria.

Toxoplasma gondii

Toxoplasma gondii is an obligate intracellular parasite and is the causative agent of toxoplasmosis (272). In most, T. gondii infection remains asymptomatic, whereas devastating diseases can occur in immunosuppressed individuals, causing infections in the brain and other tissues (273). As an apicomplexan, T. gondii has evolved specialized secretory organelles, including the rhoptries (ROPs) and dense granules (GRAs), which are designated to inject effector molecules into the host cell (274). The parasite can also invade and replicate in host cell by secreting ROP effector proteins and building a parasitophorous vacuole (PV) (Figure 8C), with the injection of GRA molecules into the cell cytosol to promote parasite growth (275). Profilin was identified from T. gondii as a PAMP recognized by murine Toll-like receptor (TLR)11/12 (276–278) (Figure 8C). Innate detection of T. gondii induces IL-12 production in both dendritic cell and macrophage to directly sense and recognize parasite-derived molecules (Figure 8C). Ripk3^-/-Casp8^-/- mice succumbed to invasion with T. gondii that was rescued with exogenous IL-12 (239). Caspase-8 is an essential regulator of cell apoptosis and is indispensable for optimal transcription of inflammatory defense genes such as il12 and il1β (239). Caspase-8 is an upstream regulator of caspase-3 that control cell apoptosis, while preventing RIPK3-MLKL-dependent necroptosis (Figure 8C). By using a small-molecule inhibitor to block TGFβ-activated kinase 1 (TAK1), the activation of caspase-8 was discovered to induce both GSDMD and GSDME cleavage in murine macrophages, causing cell pyroptosis (68). Additionally, caspase-8 was found to initiate NLRP3 inflammasomes in macrophages (240) that might serve as a compensatory pathway when caspase-1 activity is inhibited (170, 237). More work needs to be conducted on how T. gondii regulates caspase-8 activity and if GSDMD/GSDME pores mediates IL-12 release during this process (Figure 8C and Table 1).

T. gondii-induced macrophage death occurs via a guanylate binding protein (GBP) dependent event independent of GSDMD to promote apoptosis (279). GBP1 was found to be targeted in Salmonella-containing vacuoles to facilitate caspase-4 recruitment causing its activation and pyroptosis. These finding suggested an immune role for GBPs as a conduit for not only pyroptosis, but also apoptosis (279). T. gondii stimulation in human monocytes stimulates the Syk-CARD9/MALT-1-NF-κB signaling pathway and activation of the NLRP3 inflammasome to release IL-1β in a cell death- and GSDMD-independent manner (280). In contrast, T. gondii infection in microglia elicits NF-κB signaling to mediate pro-inflammatory cytokine secretion in innate host defence. Other studies have shown that GSDMD dependent IL-1α but not IL-1β release in microglia impaired parasite control and dysregulated immune cell infiltration. Unlike IL-1β, IL-1α functions as an alarmin molecule directly released without processing upon sensing invasive signals, acting as a rapid initiator in inflammatory response (281). IL-1α and IL-1β both process through the same receptor (IL-1R) (282) (Figure 8C). It was concluded that microglia act differently from macrophages as they can release the alarmin IL-1α to promote neuroinflammation and parasite control in T. gondii infection though they are present in the identical microenvironment in the central nervous system (241). Furthermore, IL-1R1 is primarily expressed on blood vasculature in the brain, and the pro-inflammatory response triggers in the brain during chronic T. gondii infection is regulated through IL-1α, but not IL-1β, since brain-resident microglia lack an NF-κB signature compared to monocyte-differentiated macrophages (241). In GSDMD KO there is a robust increase in T. gondii cyst burden six weeks post infection compared to wild-type mice, indicating an inflammasome-mediated neuroinflammation requires GSDMD to control T. gondii in the brain (241). However, studies are still needed to determine what role IL-1R could play in controlling T. gondii infection in the gut and macrophages. Activating the P2X₇ receptor with extracellular ATP in T. gondii-stimulated macrophages enhanced parasite clearance by producing ROS and lysosome fusion with parasitophorous vacuole, forming a phagolysosome (238). Extracellular ATP also activated the NLRP3 inflammasome to potentiate IL-1β secretion by recruiting caspase-1. IL-1β released in the extracellular milieu binds to its receptor accelerating T. gondii eradication through mitochondrial ROS production (Figure 8C). T. gondii-mediated activation of the inflammasome results in caspase-1-mediated processing of IL-1α, IL-1β and IL-18 and pyroptosis (Figure 8C).

Leishmania

Leishmaniasis is a vector-borne parasitic inflammatory disease caused by the protozoan parasite of the Leishmania genus. This disease affects millions of people, over 88 countries worldwide, especially prevalent in tropical and subtropical areas of the world (283). Self-healing cutaneous and debilitating visceral leishmaniasis affect approximately 1.5 million people globally (283, 284).

The parasite exists extracellularly as flagellated promastigotes in sand flies (283). Leishmania spp. interact with a range of cells, including neutrophils, monocytes, and macrophages, where the parasites differentiate into amastigotes and replicate inside the parasitophorous vacuole (283) (Figure 8D). Inflammasome activation is a signature event of leishmaniasis and is protective and responsible for the restriction of parasite replication in macrophages (242, 285). All different species of Leishmania can activate the NLRP3 inflammasome via K⁺ efflux and cathepsins to release IL-1β (242) (Figure 8D). Upon phagocytosis, the parasite turns on the C-type lectin receptor: Dectin-1, which elicits a Syk-dependent signaling pathway that results in ROS generation to contribute to NLRP3 inflammasome activation (243) (Figure 8D). More recently, it was shown that Leishmania lipophosphoglycan (LPG) can trigger the activation of caspase-11 to promote GSDMD pore formation, IL-1β secretion and pyroptotic cell death (244) (Figure 8D).

Receptor interacting protein kinase 1 (RIPK1) is a critical kinase that mediates necroptotic cell death following activation of various cell death receptors and TLRs (245). Human visceral leishmaniasis displayed increased serum levels of heme (Figure 8D), which is generated by hemoglobin catabolism, and is a potent stimulator of necroptotic macrophage (245). By examining the correlation between heme and necroptosis, it was found that heme strongly prevented Leishmania replication in BMDMs, and blocking RIPK1 kinase activity upregulated Leishmania replication without the presence of heme (245). Since GSDMD can be cleaved by RIPK1 (Table 1) and RIPK1 kinase activity is required for IL-1β expression in response to Leishmania (245), it would be of interest to detect if any crosstalk between necroptosis and pyroptosis exists in the presence of Leishmania. In addition, how pyroptosis affects parasite survival and virulence remains to be elucidated. Interestingly, it was reported that the host cell secretory pathway can export Leishmania zinc-metalloprotease GP63 and LPG (286) out of the vacuole, suggesting these virulent factors could act as the upstream regulator for caspase-11 activation. On the contrary, Leishmania can negatively regulate inflammasome activation by using GP63 to block PKC signaling in human monocytes, avoiding ROS generation, inflammasome activation and IL-1β production (287).

Concluding Remarks

A protective role of inflammasome signaling and inflammatory cytokine release has been determined against protozoan parasites, particularly in the acute phase of infection. It is worth noting that in the past several decades new modes of regulated cell death have emerged to involve inflammatory form of necroptosis and pyroptosis, and other inflammatory manners of caspase-independent programmed cell death. Inhibiting pyroptosis ameliorates disease, including septic shock and autoinflammation, conversely, it can be detrimental for infections. The key roles of GSDMs in autoimmune and inflammatory diseases, infection, deafness and cancer are evolving, which reveals possible novel therapeutic avenues (76, 113, 288, 289). However, of note, the non-pyroptotic function of GSDMD has been uncovered in Eh-induced hyperactivated macrophages (22), and in GSDMD deficient LS174T cells (goblet cell line) that displayed vigorous reduction in MUC2 secretion when stimulated with mucus secretagogues such as ATP, histamine and PMA (290), suggesting a significant non-pyroptotic role of GSDMD in regulating cortical actin cytoskeleton disassembly during mucin granule exocytosis (291). By proteomics analysis, we determined SNAP23 is highly involved in membrane trafficking and is downregulated in Eh-induced hyperactivated macrophages (22), implying potential relevance may exist between exocytosis (membrane repair response) and conversion between hyperactivation and pyroptosis in macrophage. Mechanistically, if GSDM pores are effectively repaired by membrane repair pathways, pyroptotic cells might transform into non-pyroptotic or hyperactivated counterparts, whereas if GSDM pores keep releasing inflammatory cytokines and ions, the cell would finally burst. Thus, studying the mechanisms of the membrane repair system might shed light on defining the non-pyroptotic roles of GSDMs in the pathogenesis of protozoan parasites.

Pyroptosis and the connection between pyroptosis and apoptosis need further investigation. Caspase-3 as the common main protease that triggers the cleavage of GSDME (65) is the key determinant of which mode of programmed cell death pathway the cell follows. GSDME can be exploited as a master switch molecule in shifting between apoptosis and pyroptosis. The level of GSDME expression determines the fate of the cell: cells that express adequate GSDME trigger pyroptosis, while cells expressing insufficient GSDME elicit apoptosis (74). Moreover, GSDME cleavage particularly depends on caspase-3 and not caspase-7 to switch TNF-induced apoptosis to pyroptosis in HeLa cells (74). Since GSDME enhances caspase-3/7 activation in apoptotic cell death through targeting the mitochondria to release cytochrome c (99), we predict an inflammatory role of GSDME to trigger pyroptotic cell death is vital in alleviating protozoan parasite infections (Figure 8). Therefore, by targeting caspase-3 or GSDME, it holds much hope to explore the mechanism of development and treatment in inflammatory disorders, and to search new targets and strategies that are feasible for clinical use.

Recent studies have significantly advanced our understanding of the mechanisms and physiological roles of pyroptosis. Overall, there is a remarkable knowledge gap between GSDMs and protozoan parasite infection. More in-depth research needs to be focused on delineating how diverse immune cells regulate GSDMs pore-forming activity differently, how parasites manipulate GSDMs pore-forming activity to prevent being eradicated, what determines whether GSDMD cleavage induces hyperactivation or pyroptosis, how GSDMs pores initiate membrane repair, and what are the differences between extracellular and intracellular parasites in triggering GSDMs pore formation. Given the primary function of GSDMs in combating protozoan parasites, the search for GSDM-regulating pore-forming activity is likely to be extraordinarily developed in the future.

Funding

This work was funded by a Discovery Grant (RGPIN/04139-2019) from the Natural Sciences and Engineering Research Council of Canada and project grants from the Canadian Institutes of Health Research (PJT-173551, PJT-162284) awarded to KC.

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

• 1

  MortimerLMoreauFCornickSChadeeK. The NLRP3 Inflammasome Is a Pathogen Sensor for Invasive Entamoeba histolytica via Activation of Alpha5beta1 Integrin at the Macrophage-Amebae Intercellular Junction. PLoS Pathog (2015) 11:5:e1004887. doi: 10.1371/journal.ppat.1004887

  • CrossRef
  • Google Scholar

• 2

  StanleySLJr. Amoebiasis. Lancet (2003) 361:93621025–34. doi: 10.1016/S0140-6736(03)12830-9

  • CrossRef
  • Google Scholar

• 3

  MortimerLChadeeK. The Immunopathogenesis of Entamoeba histolytica. Exp Parasitol (2010) 126:3366–80. doi: 10.1016/j.exppara.2010.03.005

  • CrossRef
  • Google Scholar

• 4

  RalstonKSPetriWAJr. Tissue Destruction and Invasion by Entamoeba histolytica. Trends Parasitol (2011) 27:6254–63. doi: 10.1016/j.pt.2011.02.006

  • CrossRef
  • Google Scholar

• 5

  Mortality GBDCauses of Death C. Global, Regional, and National Age-Sex Specific All-Cause and Cause-Specific Mortality for 240 Causes of Death, 1990-2013: A Systematic Analysis for the Global Burden of Disease Study 2013. Lancet (2015) 385:9963117–71. doi: 10.1016/S0140-6736(14)61682-2

  • CrossRef
  • Google Scholar

• 6

  CornickSTawiahAChadeeK. Roles and Regulation of the Mucus Barrier in the Gut. Tissue Barriers (2015) 3:1–2.e982426. doi: 10.4161/21688370.2014.982426

  • CrossRef
  • Google Scholar

• 7

  TurnerJR. Intestinal Mucosal Barrier Function in Health and Disease. Nat Rev Immunol (2009) 9:11799–809. doi: 10.1038/nri2653

  • CrossRef
  • Google Scholar

• 8

  JohanssonMEPhillipsonMPeterssonJVelcichAHolmLHanssonGC. The Inner of the Two Muc2 Mucin-Dependent Mucus Layers in Colon Is Devoid of Bacteria. Proc Natl Acad Sci USA (2008) 105:3915064–9. doi: 10.1073/pnas.0803124105

  • CrossRef
  • Google Scholar

• 9

  JohanssonMELarssonJMHanssonGC. The Two Mucus Layers of Colon Are Organized by the MUC2 Mucin, Whereas the Outer Layer Is a Legislator of Host-Microbial Interactions. Proc Natl Acad Sci USA (2011) 108 Suppl 1:4659–65. doi: 10.1073/pnas.1006451107

  • CrossRef
  • Google Scholar

• 10

  MortimerLMoreauFCornickSChadeeK. Gal-Lectin-Dependent Contact Activates the Inflammasome by Invasive Entamoeba histolytica. Mucosal Immunol (2014) 7:4829–41. doi: 10.1038/mi.2013.100

  • CrossRef
  • Google Scholar

• 11

  ChadeeKPetriWAJr.InnesDJRavdinJI. Rat and Human Colonic Mucins Bind to and Inhibit Adherence Lectin of Entamoeba histolytica. J Clin Invest (1987) 80:51245–54. doi: 10.1172/JCI113199

  • CrossRef
  • Google Scholar

• 12

  DodsonJMLenkowskiPWJr.EubanksACJacksonTFNapodanoJLyerlyDMet al. Infection and Immunity Mediated by the Carbohydrate Recognition Domain of the Entamoeba histolytica Gal/GalNAc Lectin. J Infect Dis (1999) 179:2460–6. doi: 10.1086/314610

  • CrossRef
  • Google Scholar

• 13

  BrachaRMirelmanD. Adherence and Ingestion of Escherichia Coli Serotype 055 by Trophozoites of Entamoeba histolytica. Infect Immun (1983) 40:3882–7. doi: 10.1128/IAI.40.3.882-887.1983

  • CrossRef
  • Google Scholar

• 14

  RavdinJIGuerrantRL. Role of Adherence in Cytopathogenic Mechanisms of Entamoeba histolytica. Study With Mammalian Tissue Culture Cells and Human Erythrocytes. J Clin Invest (1981) 68:51305–13. doi: 10.1172/jci110377

  • CrossRef
  • Google Scholar

• 15

  PetriWAJr.SmithRDSchlesingerPHMurphyCFRavdinJI. Isolation of the Galactose-Binding Lectin That Mediates the In Vitro Adherence of Entamoeba histolytica. J Clin Invest (1987) 80:51238–44. doi: 10.1172/JCI113198

  • CrossRef
  • Google Scholar

• 16

  MoncadaDKellerKChadeeK. Entamoeba histolytica Cysteine Proteinases Disrupt the Polymeric Structure of Colonic Mucin and Alter Its Protective Function. Infect Immun (2003) 71:2838–44. doi: 10.1128/iai.71.2.838-844.2003

  • CrossRef
  • Google Scholar

• 17

  LidellMEMoncadaDMChadeeKHanssonGC. Entamoeba histolytica Cysteine Proteases Cleave the MUC2 Mucin in its C-Terminal Domain and Dissolve the Protective Colonic Mucus Gel. Proc Natl Acad Sci USA (2006) 103:249298–303. doi: 10.1073/pnas.0600623103

  • CrossRef
  • Google Scholar

• 18

  CornickSMoreauFChadeeK. Entamoeba histolytica Cysteine Proteinase 5 Evokes Mucin Exocytosis From Colonic Goblet Cells via Alphavbeta3 Integrin. PLoS Pathog (2016) 12(4):e1005579. doi: 10.1371/journal.ppat.1005579

  • CrossRef
  • Google Scholar

• 19

  ShiJZhaoYWangKShiXWangYHuangHet al. Cleavage of GSDMD by Inflammatory Caspases Determines Pyroptotic Cell Death. Nature (2015) 526:7575660–5. doi: 10.1038/nature15514

  • CrossRef
  • Google Scholar

• 20

  KayagakiNStoweIBLeeBLO'RourkeKAndersonKWarmingSet al. Caspase-11 Cleaves Gasdermin D for Non-Canonical Inflammasome Signalling. Nature (2015) 526:7575666–71. doi: 10.1038/nature15541

  • CrossRef
  • Google Scholar

• 21

  QuachJMoreauFSandallCChadeeK. Entamoeba histolytica-Induced IL-1beta Secretion is Dependent on Caspase-4 and Gasdermin D. Mucosal Immunol (2019) 12:2323–39. doi: 10.1038/s41385-018-0101-9

  • CrossRef
  • Google Scholar

• 22

  WangSMoreauFChadeeK. The Colonic Pathogen Entamoeba histolytica Activates Caspase-4/1 That Cleaves the Pore-Forming Protein Gasdermin D to Regulate IL-1β Secretion. PLoS Pathog (2022) 18(3):e1010415. doi: 10.1371/journal.ppat.1010415

  • CrossRef
  • Google Scholar

• 23

  KayagakiNKornfeldOSLeeBLStoweIBO'RourkeKLiQet al. NINJ1 Mediates Plasma Membrane Rupture During Lytic Cell Death. Nature (2021) 591:7848131–6. doi: 10.1038/s41586-021-03218-7

  • CrossRef
  • Google Scholar

• 24

  MartinonFMayorATschoppJ. The Inflammasomes: Guardians of the Body. Annu Rev Immunol (2009) 27:229–65. doi: 10.1146/annurev.immunol.021908.132715

  • CrossRef
  • Google Scholar

• 25

  DinarelloCA. Interleukin-1 in the Pathogenesis and Treatment of Inflammatory Diseases. Blood (2011) 117:143720–32. doi: 10.1182/blood-2010-07-273417

  • CrossRef
  • Google Scholar

• 26

  FranchiLEigenbrodTNunezG. Cutting Edge: TNF-Alpha Mediates Sensitization to ATP and Silica via the NLRP3 Inflammasome in the Absence of Microbial Stimulation. J Immunol (2009) 183:2792–6. doi: 10.4049/jimmunol.0900173

  • CrossRef
  • Google Scholar

• 27

  JinCFlavellRA. Molecular Mechanism of NLRP3 Inflammasome Activation. J Clin Immunol (2010) 30:5628–31. doi: 10.1007/s10875-010-9440-3

  • CrossRef
  • Google Scholar

• 28

  SchroderKTschoppJ. The Inflammasomes. Cell (2010) 140:6821–32. doi: 10.1016/j.cell.2010.01.040

  • CrossRef
  • Google Scholar

• 29

  ThornberryNABullHGCalaycayJRChapmanKTHowardADKosturaMJet al. A Novel Heterodimeric Cysteine Protease Is Required for Interleukin-1 Beta Processing in Monocytes. Nature (1992) 356:6372768–74. doi: 10.1038/356768a0

  • CrossRef
  • Google Scholar

• 30

  KayagakiNWarmingSLamkanfiMVande WalleLLouieSDongJet al. Non-Canonical Inflammasome Activation Targets Caspase-11. Nature (2011) 479:7371117–21. doi: 10.1038/nature10558

  • CrossRef
  • Google Scholar

• 31

  ChowdhuryITharakanBBhatGK. Caspases - an Update. Comp Biochem Physiol B Biochem Mol Biol (2008) 151:110–27. doi: 10.1016/j.cbpb.2008.05.010

  • CrossRef
  • Google Scholar

• 32

  RamirezMLGSalvesenGS. A Primer on Caspase Mechanisms. Semin Cell Dev Biol (2018) 82:79–85. doi: 10.1016/j.semcdb.2018.01.002

  • CrossRef
  • Google Scholar

• 33

  ScottAMSalehM. The Inflammatory Caspases: Guardians Against Infections and Sepsis. Cell Death Differ (2007) 14:123–31. doi: 10.1038/sj.cdd.4402026

  • CrossRef
  • Google Scholar

• 34

  MartinonFBurnsKTschoppJ. The Inflammasome: A Molecular Platform Triggering Activation of Inflammatory Caspases and Processing of proIL-Beta. Mol Cell (2002) 10:2417–26. doi: 10.1016/s1097-2765(02)00599-3

  • CrossRef
  • Google Scholar

• 35

  KamensJPaskindMHuguninMTalanianRVAllenHBanachDet al. Identification and Characterization of ICH-2, a Novel Member of the Interleukin-1 Beta-Converting Enzyme Family of Cysteine Proteases. J Biol Chem (1995) 270:2515250–6. doi: 10.1074/jbc.270.25.15250

  • CrossRef
  • Google Scholar

• 36

  SollbergerGStrittmatterGEKistowskaMFrenchLEBeerHD. Caspase-4 is Required for Activation of Inflammasomes. J Immunol (2012) 188:41992–2000. doi: 10.4049/jimmunol.1101620

  • CrossRef
  • Google Scholar

• 37

  CheungKTSzeDMChanKHLeungPH. Involvement of Caspase-4 in IL-1 Beta Production and Pyroptosis in Human Macrophages During Dengue Virus Infection. Immunobiology (2018) 223:4–5356-64. doi: 10.1016/j.imbio.2017.10.044

  • CrossRef
  • Google Scholar

• 38

  ShiJZhaoYWangYGaoWDingJLiPet al. Inflammatory Caspases Are Innate Immune Receptors for Intracellular LPS. Nature (2014) 514:7521187–92. doi: 10.1038/nature13683

  • CrossRef
  • Google Scholar

• 39

  KnodlerLACrowleySMShamHPYangHWrandeMMaCet al. Noncanonical Inflammasome Activation of Caspase-4/Caspase-11 Mediates Epithelial Defenses Against Enteric Bacterial Pathogens. Cell Host Microbe (2014) 16:2249–56. doi: 10.1016/j.chom.2014.07.002

  • CrossRef
  • Google Scholar

• 40

  TamuraMTanakaSFujiiTAokiAKomiyamaHEzawaKet al. Members of a Novel Gene Family, Gsdm, are Expressed Exclusively in the Epithelium of the Skin and Gastrointestinal Tract in a Highly Tissue-Specific Manner. Genomics (2007) 89:5618–29. doi: 10.1016/j.ygeno.2007.01.003

  • CrossRef
  • Google Scholar

• 41

  BrozPPelegrinPShaoF. The Gasdermins, a Protein Family Executing Cell Death and Inflammation. Nat Rev Immunol (2020) 20:3143–57. doi: 10.1038/s41577-019-0228-2

  • CrossRef
  • Google Scholar

• 42

  DingJWangKLiuWSheYSunQShiJet al. Pore-Forming Activity and Structural Autoinhibition of the Gasdermin Family. Nature (2016) 535:7610111–6. doi: 10.1038/nature18590

  • CrossRef
  • Google Scholar

• 43

  LiuXZhangZRuanJPanYMagupalliVGWuHet al. Inflammasome-Activated Gasdermin D Causes Pyroptosis by Forming Membrane Pores. Nature (2016) 535:7610153–8. doi: 10.1038/nature18629

  • CrossRef
  • Google Scholar

• 44

  SborgiLRuhlSMulvihillEPipercevicJHeiligRStahlbergHet al. GSDMD Membrane Pore Formation Constitutes the Mechanism of Pyroptotic Cell Death. EMBO J (2016) 35:161766–78. doi: 10.15252/embj.201694696

  • CrossRef
  • Google Scholar

• 45

  AgliettiRAEstevezAGuptaARamirezMGLiuPSKayagakiNet al. GsdmD P30 Elicited by Caspase-11 During Pyroptosis Forms Pores in Membranes. Proc Natl Acad Sci U S A (2016) 113:287858–63. doi: 10.1073/pnas.1607769113

  • CrossRef
  • Google Scholar

• 46

  SaekiNKuwaharaYSasakiHSatohHShiroishiT. Gasdermin (Gsdm) Localizing to Mouse Chromosome 11 Is Predominantly Expressed in Upper Gastrointestinal Tract But Significantly Suppressed in Human Gastric Cancer Cells. Mamm Genome (2000) 11:9718–24. doi: 10.1007/s003350010138

  • CrossRef
  • Google Scholar

• 47

  RunkelFMarquardtAStoegerCKochmannESimonDKohnkeBet al. The Dominant Alopecia Phenotypes Bareskin, Rex-Denuded, and Reduced Coat 2 Are Caused by Mutations in Gasdermin 3. Genomics (2004) 84:5824–35. doi: 10.1016/j.ygeno.2004.07.003

  • CrossRef
  • Google Scholar

• 48

  YuYZhangCZhouGWuSQuXWeiHet al. Gene Expression Profiling in Human Fetal Liver and Identification of Tissue- and Developmental-Stage-Specific Genes Through Compiled Expression Profiles and Efficient Cloning of Full-Length cDNAs. Genome Res (2001) 11:81392–403. doi: 10.1101/gr.175501

  • CrossRef
  • Google Scholar

• 49

  TanakaSMizushinaYKatoYTamuraMShiroishiT. Functional Conservation of Gsdma Cluster Genes Specifically Duplicated in the Mouse Genome. G3 (Bethesda) (2013) 3:101843–50. doi: 10.1534/g3.113.007393

  • CrossRef
  • Google Scholar

• 50

  LunnyDPWeedENolanPMMarquardtAAugustinMPorterRM. Mutations in Gasdermin 3 Cause Aberrant Differentiation of the Hair Follicle and Sebaceous Gland. J Invest Dermatol (2005) 124:3615–21. doi: 10.1111/j.0022-202X.2005.23623.x

  • CrossRef
  • Google Scholar

• 51

  KumarSRathkolbBBuddeBSNurnbergPde AngelisMHAignerBet al. Gsdma3(I359N) Is a Novel ENU-Induced Mutant Mouse Line for Studying the Function of Gasdermin A3 in the Hair Follicle and Epidermis. J Dermatol Sci (2012) 67:3190–2. doi: 10.1016/j.jdermsci.2012.05.001

  • CrossRef
  • Google Scholar

• 52

  DengWBaiYDengFPanYMeiSZhengZet al. Streptococcal Pyrogenic Exotoxin B Cleaves GSDMA and Triggers Pyroptosis. Nature (2022) 602:7897496–502. doi: 10.1038/s41586-021-04384-4

  • CrossRef
  • Google Scholar

• 53

  LiJZhouYYangTWangNLianXYangL. Gsdma3 Is Required for Hair Follicle Differentiation in Mice. Biochem Biophys Res Commun (2010) 403:118–23. doi: 10.1016/j.bbrc.2010.10.094

  • CrossRef
  • Google Scholar

• 54

  SatoHKoideTMasuyaHWakanaSSagaiTUmezawaAet al. A New Mutation Rim3 Resembling Re(den) Is Mapped Close to Retinoic Acid Receptor Alpha (Rara) Gene on Mouse Chromosome 11. Mamm Genome (1998) 9:120–5. doi: 10.1007/s003359900673

  • CrossRef
  • Google Scholar

• 55

  ZhouZHeHWangKShiXWangYSuYet al. Granzyme A From Cytotoxic Lymphocytes Cleaves GSDMB to Trigger Pyroptosis in Target Cells. Science (2020) 368:6494. doi: 10.1126/science.aaz7548

  • CrossRef
  • Google Scholar

• 56

  DasSMillerMBeppuAKMuellerJMcGeoughMDVuongCet al. GSDMB Induces an Asthma Phenotype Characterized by Increased Airway Responsiveness and Remodeling Without Lung Inflammation. Proc Natl Acad Sci USA (2016) 113:4613132–7. doi: 10.1073/pnas.1610433113

  • CrossRef
  • Google Scholar

• 57

  RanaNPriviteraGKondolfHCBulekKLechugaSDe SalvoCet al. GSDMB Is Increased in IBD and Regulates Epithelial Restitution/Repair Independent of Pyroptosis. Cell (2022) 185:2283–98.e17. doi: 10.1016/j.cell.2021.12.024

  • CrossRef
  • Google Scholar

• 58

  HuYJinSChengLLiuGJiangQ. Autoimmune Disease Variants Regulate GSDMB Gene Expression in Human Immune Cells and Whole Blood. Proc Natl Acad Sci USA (2017) 114:38:E7860–E2. doi: 10.1073/pnas.1712127114

  • CrossRef
  • Google Scholar

• 59

  VerlaanDJBerlivetSHunninghakeGMMadoreAMLariviereMMoussetteSet al. Allele-Specific Chromatin Remodeling in the ZPBP2/GSDMB/ORMDL3 Locus Associated With the Risk of Asthma and Autoimmune Disease. Am J Hum Genet (2009) 85:3377–93. doi: 10.1016/j.ajhg.2009.08.007

  • CrossRef
  • Google Scholar

• 60

  KangMJYuHSSeoJHKimHYJungYHKimYJet al. GSDMB/ORMDL3 Variants Contribute to Asthma Susceptibility and Eosinophil-Mediated Bronchial Hyperresponsiveness. Hum Immunol (2012) 73:9954–9. doi: 10.1016/j.humimm.2012.06.009

  • CrossRef
  • Google Scholar

• 61

  ChenQShiPWangYZouDWuXWangDet al. GSDMB Promotes non-Canonical Pyroptosis by Enhancing Caspase-4 Activity. J Mol Cell Biol (2019) 11:6496–508. doi: 10.1093/jmcb/mjy056

  • CrossRef
  • Google Scholar

• 62

  WeiJXuZChenXWangXZengSQianLet al. Overexpression of GSDMC Is a Prognostic Factor for Predicting a Poor Outcome in Lung Adenocarcinoma. Mol Med Rep (2020) 21:1360–70. doi: 10.3892/mmr.2019.10837

  • CrossRef
  • Google Scholar

• 63

  CuiYQMengFZhanWLDaiZTLiaoX. High Expression of GSDMC Is Associated With Poor Survival in Kidney Clear Cell Cancer. BioMed Res Int (2021) 2021:5282894. doi: 10.1155/2021/5282894

  • CrossRef
  • Google Scholar

• 64

  XiRMontagueJLinXLuCLeiWTanakaKet al. Up-Regulation of Gasdermin C in Mouse Small Intestine Is Associated with Lytic Cell Death in Enterocytes in Worm-Induced Type 2 Immunity. Proc Natl Acad Sci USA (2021) 118:30. doi: 10.1073/pnas.2026307118

  • CrossRef
  • Google Scholar

• 65

  HouJZhaoRXiaWChangCWYouYHsuJMet al. PD-L1-Mediated Gasdermin C Expression Switches Apoptosis to Pyroptosis in Cancer Cells and Facilitates Tumour Necrosis. Nat Cell Biol (2020) 22:101264–75. doi: 10.1038/s41556-020-0575-z

  • CrossRef
  • Google Scholar

• 66

  WatabeKItoAAsadaHEndoYKobayashiTNakamotoKet al. Structure, Expression and Chromosome Mapping of MLZE, a Novel Gene Which Is Preferentially Expressed in Metastatic Melanoma Cells. Jpn J Cancer Res (2001) 92:2140–51. doi: 10.1111/j.1349-7006.2001.tb01076.x

  • CrossRef
  • Google Scholar

• 67

  OrningPWengDStarheimKRatnerDBestZLeeBet al. Pathogen Blockade of TAK1 Triggers Caspase-8-Dependent Cleavage of Gasdermin D and Cell Death. Science (2018) 362:64181064–9. doi: 10.1126/science.aau2818

  • CrossRef
  • Google Scholar

• 68

  SarhanJLiuBCMuendleinHILiPNilsonRTangAYet al. Caspase-8 Induces Cleavage of Gasdermin D to Elicit Pyroptosis During Yersinia Infection. Proc Natl Acad Sci USA (2018) 115:46E10888–E97. doi: 10.1073/pnas.1809548115

  • CrossRef
  • Google Scholar

• 69

  SollbergerGChoidasABurnGLHabenbergerPDi LucreziaRKordesSet al. Gasdermin D Plays a Vital Role in the Generation of Neutrophil Extracellular Traps. Sci Immunol (2018) 3:26. doi: 10.1126/sciimmunol.aar6689

  • CrossRef
  • Google Scholar

• 70

  ChenKWMonteleoneMBoucherDSollbergerGRamnathDCondonNDet al. Noncanonical Inflammasome Signaling Elicits Gasdermin D-Dependent Neutrophil Extracellular Traps. Sci Immunol (2018) 3:26. doi: 10.1126/sciimmunol.aar6676

  • CrossRef
  • Google Scholar

• 71

  LiSWuYYangDWuCMaCLiuXet al. Gasdermin D in Peripheral Myeloid Cells Drives Neuroinflammation in Experimental Autoimmune Encephalomyelitis. J Exp Med (2019) 216:112562–81. doi: 10.1084/jem.20190377

  • CrossRef
  • Google Scholar

• 72

  KannegantiAMalireddiRKSSaavedraPHVVande WalleLVan GorpHKambaraHet al. GSDMD Is Critical for Autoinflammatory Pathology in a Mouse Model of Familial Mediterranean Fever. J Exp Med (2018) 215:61519–29. doi: 10.1084/jem.20172060

  • CrossRef
  • Google Scholar

• 73

  BegumSMoreauFLeon CoriaAChadeeK. Entamoeba histolytica Stimulates the Alarmin Molecule HMGB1 from Macrophages to Amplify Innate Host Defenses. Mucosal Immunol (2020) 13:2344–56. doi: 10.1038/s41385-019-0233-6

  • CrossRef
  • Google Scholar

• 74

  WangYGaoWShiXDingJLiuWHeHet al. Chemotherapy Drugs Induce Pyroptosis Through Caspase-3 Cleavage of a Gasdermin. Nature (2017) 547:766199–103. doi: 10.1038/nature22393

  • CrossRef
  • Google Scholar

• 75

  RogersCFernandes-AlnemriTMayesLAlnemriDCingolaniGAlnemriES. Cleavage of DFNA5 by Caspase-3 During Apoptosis Mediates Progression to Secondary Necrotic/Pyroptotic Cell Death. Nat Commun (2017) 8:14128. doi: 10.1038/ncomms14128

  • CrossRef
  • Google Scholar

• 76

  ZhangZZhangYXiaSKongQLiSLiuXet al. Gasdermin E Suppresses Tumour Growth by Activating Anti-Tumour Immunity. Nature (2020) 579:7799415–20. doi: 10.1038/s41586-020-2071-9

  • CrossRef
  • Google Scholar

• 77

  BischoffAMLuijendijkMWHuygenPLvan DuijnhovenGDe LeenheerEMOudesluijsGGet al. A Novel Mutation Identified in the DFNA5 Gene in a Dutch Family: A Clinical and Genetic Evaluation. Audiol Neurootol (2004) 9:134–46. doi: 10.1159/000074185

  • CrossRef
  • Google Scholar

• 78

  ChengJHanDYDaiPSunHJTaoRSunQet al. A Novel DFNA5 Mutation, IVS8+4 A>G, in the Splice Donor Site of Intron 8 Causes Late-Onset non-Syndromic Hearing Loss in a Chinese Family. Clin Genet (2007) 72:5471–7. doi: 10.1111/j.1399-0004.2007.00889.x

  • CrossRef
  • Google Scholar

• 79

  Li-YangMNShenXFWeiQJYaoJLuYJCaoXet al. IVS8+1 DelG, a Novel Splice Site Mutation Causing DFNA5 Deafness in a Chinese Family. Chin Med J (Engl) (2015) 128:182510–5. doi: 10.4103/0366-6999.164980

  • CrossRef
  • Google Scholar

• 80

  YuCMengXZhangSZhaoGHuLKongX. A 3-Nucleotide Deletion in the Polypyrimidine Tract of Intron 7 of the DFNA5 Gene Causes Nonsyndromic Hearing Impairment in a Chinese Family. Genomics (2003) 82:5575–9. doi: 10.1016/s0888-7543(03)00175-7

  • CrossRef
  • Google Scholar

• 81

  ParkHJChoHJBaekJIBen-YosefTKwonTJGriffithAJet al. Evidence for a Founder Mutation Causing DFNA5 Hearing Loss in East Asians. J Hum Genet (2010) 55:159–62. doi: 10.1038/jhg.2009.114

  • CrossRef
  • Google Scholar

• 82

  NishioANoguchiYSatoTNaruseTKKimuraATakagiAet al. A DFNA5 Mutation Identified in Japanese Families with Autosomal Dominant Hereditary Hearing Loss. Ann Hum Genet (2014) 78:283–91. doi: 10.1111/ahg.12053

  • CrossRef
  • Google Scholar

• 83

  JiangSGuHZhaoYSunL. Teleost Gasdermin E is Cleaved by Caspase 1, 3, and 7 and Induces Pyroptosis. J Immunol (2019) 203:51369–82. doi: 10.4049/jimmunol.1900383

  • CrossRef
  • Google Scholar

• 84

  Forn-CuniGMeijerAHVarelaM. Zebrafish in Inflammasome Research. Cells (2019) 8:8. doi: 10.3390/cells8080901

  • CrossRef
  • Google Scholar

• 85

  DelmaghaniSdel CastilloFJMichelVLeiboviciMAghaieARonUet al. Mutations in the Gene Encoding Pejvakin, a Newly Identified Protein of the Afferent Auditory Pathway, Cause DFNB59 Auditory Neuropathy. Nat Genet (2006) 38:7770–8. doi: 10.1038/ng1829

  • CrossRef
  • Google Scholar

• 86

  SzklarczykDGableALLyonDJungeAWyderSHuerta-CepasJet al. STRING V11: Protein-Protein Association Networks with Increased Coverage, Supporting Functional Discovery in Genome-Wide Experimental Datasets. Nucleic Acids Res (2019) 47:D1D607–D13. doi: 10.1093/nar/gky1131

  • CrossRef
  • Google Scholar

• 87

  TanakaSTamuraMAokiAFujiiTKomiyamaHSagaiTet al. A New Gsdma3 Mutation Affecting Anagen Phase of First Hair Cycle. Biochem Biophys Res Commun (2007) 359:4902–7. doi: 10.1016/j.bbrc.2007.05.209

  • CrossRef
  • Google Scholar

• 88

  ShiPTangAXianLHouSZouDLvYet al. Loss of Conserved Gsdma3 Self-Regulation Causes Autophagy and Cell Death. Biochem J (2015) 468:2325–36. doi: 10.1042/BJ20150204

  • CrossRef
  • Google Scholar

• 89

  LaRockDLJohnsonAFWildeSSandsJSMonteiroMPLaRockCN. Group A Streptococcus Induces GSDMA-Dependent Pyroptosis in Keratinocytes. Nature (2022) 605:527–31. doi: 10.1038/s41586-022-04717-x

  • CrossRef
  • Google Scholar

• 90

  KatohMKatohM. Identification and Characterization of Human DFNA5L, Mouse Dfna5l, and Rat Dfna5l Genes in Silico. Int J Oncol (2004) 25:3765–70. doi: 10.3892/ijo.25.3.765

  • CrossRef
  • Google Scholar

• 91

  ZhangJYZhouBSunRYAiYLChengKLiFNet al. The Metabolite Alpha-KG Induces GSDMC-Dependent Pyroptosis Through Death Receptor 6-Activated Caspase-8. Cell Res (2021) 31:9980–97. doi: 10.1038/s41422-021-00506-9

  • CrossRef
  • Google Scholar

• 92

  KambaraHLiuFZhangXLiuPBajramiBTengYet al. Gasdermin D Exerts Anti-Inflammatory Effects by Promoting Neutrophil Death. Cell Rep (2018) 22:112924–36. doi: 10.1016/j.celrep.2018.02.067

  • CrossRef
  • Google Scholar

• 93

  ZhuQZhengMBalakrishnanAKarkiRKannegantiTD. Gasdermin D Promotes AIM2 Inflammasome Activation and is Required for Host Protection Against Francisella Novicida. J Immunol (2018) 201:123662–8. doi: 10.4049/jimmunol.1800788

  • CrossRef
  • Google Scholar

• 94

  WangJDeobaldKReF. Gasdermin D Protects From Melioidosis Through Pyroptosis and Direct Killing of Bacteria. J Immunol (2019) 202:123468–73. doi: 10.4049/jimmunol.1900045

  • CrossRef
  • Google Scholar

• 95

  DuboisHSorgeloosFSarvestaniSTMartensLSaeysYMackenzieJMet al. Nlrp3 Inflammasome Activation and Gasdermin D-Driven Pyroptosis are Immunopathogenic Upon Gastrointestinal Norovirus Infection. PLoS Pathog (2019) 15:4:e1007709. doi: 10.1371/journal.ppat.1007709

  • CrossRef
  • Google Scholar

• 96

  LammertCRFrostELBellingerCEBolteACMcKeeCAHurtMEet al. AIM2 Inflammasome Surveillance of DNA Damage Shapes Neurodevelopment. Nature (2020) 580:7805647–52. doi: 10.1038/s41586-020-2174-3

  • CrossRef
  • Google Scholar

• 97

  XiaoJWangCYaoJCAlippeYXuCKressDet al. Gasdermin D Mediates the Pathogenesis of Neonatal-Onset Multisystem Inflammatory Disease in Mice. PLoS Biol (2018) 16:11:e3000047. doi: 10.1371/journal.pbio.3000047

  • CrossRef
  • Google Scholar

• 98

  OverwijkWWRestifoNP. B16 as a Mouse Model for Human Melanoma. Curr Protoc Immunol (2001) 39:1–20. doi: 10.1002/0471142735.im2001s39

  • CrossRef
  • Google Scholar

• 99

  RogersCErkesDANardoneAAplinAEFernandes-AlnemriTAlnemriES. Gasdermin Pores Permeabilize Mitochondria to Augment Caspase-3 Activation During Apoptosis and Inflammasome Activation. Nat Commun (2019) 10:11689. doi: 10.1038/s41467-019-09397-2

  • CrossRef
  • Google Scholar

• 100

  SchwanderMSczanieckaAGrilletNBaileyJSAvenariusMNajmabadiHet al. A Forward Genetics Screen in Mice Identifies Recessive Deafness Traits and Reveals That Pejvakin is Essential for Outer Hair Cell Function. J Neurosci (2007) 27:92163–75. doi: 10.1523/JNEUROSCI.4975-06.2007

  • CrossRef
  • Google Scholar

• 101

  Van LaerLPfisterMThysSVrijensKMuellerMUmansLet al. Mice Lacking Dfna5 Show a Diverging Number of Cochlear Fourth Row Outer Hair Cells. Neurobiol Dis (2005) 19:3386–99. doi: 10.1016/j.nbd.2005.01.019

  • CrossRef
  • Google Scholar

• 102

  HarrisSLKazmierczakMPangrsicTShahPChuchvaraNBarrantes-FreerAet al. Conditional Deletion of Pejvakin in Adult Outer Hair Cells Causes Progressive Hearing Loss in Mice. Neuroscience (2017) 344:380–93. doi: 10.1016/j.neuroscience.2016.12.055

  • CrossRef
  • Google Scholar

• 103

  SodermanJBerglindLAlmerS. Gene Expression-Genotype Analysis Implicates GSDMA, GSDMB, and LRRC3C as Contributors to Inflammatory Bowel Disease Susceptibility. BioMed Res Int (2015) 2015:834805. doi: 10.1155/2015/834805

  • CrossRef
  • Google Scholar

• 104

  Moreno-MoralABagnatiMKoturanSKoJHFonsecaCHarmstonNet al. Changes in Macrophage Transcriptome Associate With Systemic Sclerosis and Mediate GSDMA Contribution to Disease Risk. Ann Rheum Dis (2018) 77:4596–601. doi: 10.1136/annrheumdis-2017-212454

  • CrossRef
  • Google Scholar

• 105

  TeraoCKawaguchiTDieudePVargaJKuwanaMHudsonMet al. Transethnic Meta-Analysis Identifies GSDMA and PRDM1 as Susceptibility Genes to Systemic Sclerosis. Ann Rheum Dis (2017) 76:61150–8. doi: 10.1136/annrheumdis-2016-210645

  • CrossRef
  • Google Scholar

• 106

  YuJKangMJKimBJKwonJWSongYHChoiWAet al. Polymorphisms in GSDMA and GSDMB are Associated With Asthma Susceptibility, Atopy and BHR. Pediatr Pulmonol (2011) 46:7701–8. doi: 10.1002/ppul.21424

  • CrossRef
  • Google Scholar

• 107

  LinPHLinHYKuoCCYangLT. N-Terminal Functional Domain of Gasdermin A3 Regulates Mitochondrial Homeostasis via Mitochondrial Targeting. J BioMed Sci (2015) 22:44. doi: 10.1186/s12929-015-0152-0

  • CrossRef
  • Google Scholar

• 108

  PanganibanRASunMDahlinAParkHRKanMHimesBEet al. A Functional Splice Variant Associated With Decreased Asthma Risk Abolishes the Ability of Gasdermin B to Induce Epithelial Cell Pyroptosis. J Allergy Clin Immunol (2018) 142:51469–78.e2. doi: 10.1016/j.jaci.2017.11.040

  • CrossRef
  • Google Scholar

• 109

  FagerbergLHallstromBMOksvoldPKampfCDjureinovicDOdebergJet al. Analysis of the Human Tissue-Specific Expression by Genome-Wide Integration of Transcriptomics and Antibody-Based Proteomics. Mol Cell Proteomics (2014) 13:2397–406. doi: 10.1074/mcp.M113.035600

  • CrossRef
  • Google Scholar

• 110

  VoskoboinikIWhisstockJCTrapaniJA. Perforin and Granzymes: Function, Dysfunction and Human Pathology. Nat Rev Immunol (2015) 15:6388–400. doi: 10.1038/nri3839

  • CrossRef
  • Google Scholar

• 111

  SalehNMRajSMSmythDJWallaceCHowsonJMBellLet al. Genetic Association Analyses of Atopic Illness and Proinflammatory Cytokine Genes With Type 1 Diabetes. Diabetes Metab Res Rev (2011) 27:8838–43. doi: 10.1002/dmrr.1259

  • CrossRef
  • Google Scholar

• 112

  ZhaoCNFanYHuangJJZhangHXGaoTWangCet al. The Association of GSDMB and ORMDL3 Gene Polymorphisms With Asthma: A Meta-Analysis. Allergy Asthma Immunol Res (2015) 7:2175–85. doi: 10.4168/aair.2015.7.2.175

  • CrossRef
  • Google Scholar

• 113

  ChaoKLKulakovaLHerzbergO. Gene Polymorphism Linked to Increased Asthma and IBD Risk Alters Gasdermin-B Structure, a Sulfatide and Phosphoinositide Binding Protein. Proc Natl Acad Sci USA (2017) 114:7E1128–E37. doi: 10.1073/pnas.1616783114

  • CrossRef
  • Google Scholar

• 114

  LeoniGNeumannPASumaginRDenningTLNusratA. Wound Repair: Role of Immune-Epithelial Interactions. Mucosal Immunol (2015) 8:5959–68. doi: 10.1038/mi.2015.63

  • CrossRef
  • Google Scholar

• 115

  MiguchiMHinoiTShimomuraMAdachiTSaitoYNiitsuHet al. Gasdermin C is Upregulated by Inactivation of Transforming Growth Factor Beta Receptor Type II in the Presence of Mutated Apc, Promoting Colorectal Cancer Proliferation. PLoS One (2016) 11:11:e0166422. doi: 10.1371/journal.pone.0166422

  • CrossRef
  • Google Scholar

• 116

  WuJSunYXiongZLiuJLiHLiuYet al. Association of GSDMC Polymorphisms With Lumbar Disc Herniation Among Chinese Han Population. Int J Immunogenet (2020) 47:6546–53. doi: 10.1111/iji.12488

  • CrossRef
  • Google Scholar

• 117

  JiaWQiuKHeMSongPZhouQZhouFet al. SOAPfuse: An Algorithm for Identifying Fusion Transcripts From Paired-End RNA-Seq Data. Genome Biol (2013) 14:2R12. doi: 10.1186/gb-2013-14-2-r12

  • CrossRef
  • Google Scholar

• 118

  LiuXLiebermanJ. Knocking 'Em Dead: Pore-Forming Proteins in Immune Defense. Annu Rev Immunol (2020) 38:455–85. doi: 10.1146/annurev-immunol-111319-023800

  • CrossRef
  • Google Scholar

• 119

  RathkeyJKXiaoTSAbbottDW. Human Polymorphisms in GSDMD Alter the Inflammatory Response. J Biol Chem (2020) 295:103228–38. doi: 10.1074/jbc.RA119.010604

  • CrossRef
  • Google Scholar

• 120

  ManSMKannegantiTD. Gasdermin D: The Long-Awaited Executioner of Pyroptosis. Cell Res (2015) 25:111183–4. doi: 10.1038/cr.2015.124

  • CrossRef
  • Google Scholar

• 121

  LiuZWangCYangJZhouBYangRRamachandranRet al. Crystal Structures of the Full-Length Murine and Human Gasdermin D Reveal Mechanisms of Autoinhibition, Lipid Binding, and Oligomerization. Immunity (2019) 51:143–9.e4. doi: 10.1016/j.immuni.2019.04.017

  • CrossRef
  • Google Scholar

• 122

  LiuZWangCYangJChenYZhouBAbbottDWet al. Caspase-1 Engages Full-Length Gasdermin D Through Two Distinct Interfaces That Mediate Caspase Recruitment and Substrate Cleavage. Immunity (2020) 53:1106–14.e5. doi: 10.1016/j.immuni.2020.06.007

  • CrossRef
  • Google Scholar

• 123

  ShiJGaoWShaoF. Pyroptosis: Gasdermin-Mediated Programmed Necrotic Cell Death. Trends Biochem Sci (2017) 42:4245–54. doi: 10.1016/j.tibs.2016.10.004

  • CrossRef
  • Google Scholar

• 124

  LiuXLiebermanJ. A Mechanistic Understanding of Pyroptosis: The Fiery Death Triggered by Invasive Infection. Adv Immunol (2017) 135:81–117. doi: 10.1016/bs.ai.2017.02.002

  • CrossRef
  • Google Scholar

• 125

  SeydelKBZhangTStanleySLJr. Neutrophils Play a Critical Role in Early Resistance to Amebic Liver Abscesses in Severe Combined Immunodeficient Mice. Infect Immun (1997) 65:93951–3. doi: 10.1128/iai.65.9.3951-3953.1997

  • CrossRef
  • Google Scholar

• 126

  VelazquezCShibayama-SalasMAguirre-GarciaJTsutsumiVCalderonJ. Role of Neutrophils in Innate Resistance to Entamoeba histolytica Liver Infection in Mice. Parasite Immunol (1998) 20:6255–62. doi: 10.1046/j.1365-3024.1998.00128.x

  • CrossRef
  • Google Scholar

• 127

  HartleyMADrexlerSRonetCBeverleySMFaselN. The Immunological, Environmental, and Phylogenetic Perpetrators of Metastatic Leishmaniasis. Trends Parasitol (2014) 30:8412–22. doi: 10.1016/j.pt.2014.05.006

  • CrossRef
  • Google Scholar

• 128

  ZamboniDSLima-JuniorDS. Inflammasomes in Host Response to Protozoan Parasites. Immunol Rev (2015) 265:1156–71. doi: 10.1111/imr.12291

  • CrossRef
  • Google Scholar

• 129

  DeyRJoshiABOliveiraFPereiraLGuimaraes-CostaABSerafimTDet al. Gut Microbes Egested During Bites of Infected Sand Flies Augment Severity of Leishmaniasis via Inflammasome-Derived IL-1beta. Cell Host Microbe (2018) 23:1134–43.e6. doi: 10.1016/j.chom.2017.12.002

  • CrossRef
  • Google Scholar

• 130

  KarmakarMMinnsMGreenbergENDiaz-AponteJPestonjamaspKJohnsonJLet al. N-GSDMD Trafficking to Neutrophil Organelles Facilitates IL-1beta Release Independently of Plasma Membrane Pores and Pyroptosis. Nat Commun (2020) 11:12212. doi: 10.1038/s41467-020-16043-9

  • CrossRef
  • Google Scholar

• 131

  AvilaEESalaizaNPulidoJRodriguezMCDiaz-GodinezCLacletteJPet al. Entamoeba histolytica Trophozoites and Lipopeptidophosphoglycan Trigger Human Neutrophil Extracellular Traps. PLoS One (2016) 11:7:e0158979. doi: 10.1371/journal.pone.0158979

  • CrossRef
  • Google Scholar

• 132

  van der MeerJWVogelsMTNeteaMGKullbergBJ. Proinflammatory Cytokines and Treatment of Disease. Ann N Y Acad Sci (1998) 856:243–51. doi: 10.1111/j.1749-6632.1998.tb08331.x

  • CrossRef
  • Google Scholar

• 133

  Van LaerLHuizingEHVerstrekenMvan ZuijlenDWautersJGBossuytPJet al. Nonsyndromic Hearing Impairment is Associated With a Mutation in DFNA5. Nat Genet (1998) 20:2194–7. doi: 10.1038/2503

  • CrossRef
  • Google Scholar

• 134

  ChaiYChenDWangXWuHYangT. A Novel Splice Site Mutation in DFNA5 Causes Late-Onset Progressive non-Syndromic Hearing Loss in a Chinese Family. Int J Pediatr Otorhinolaryngol (2014) 78:81265–8. doi: 10.1016/j.ijporl.2014.05.007

  • CrossRef
  • Google Scholar

• 135

  ChenSDongCWangQZhongZQiYKeXet al. Targeted Next-Generation Sequencing Successfully Detects Causative Genes in Chinese Patients With Hereditary Hearing Loss. Genet Test Mol Biomarkers (2016) 20:11660–5. doi: 10.1089/gtmb.2016.0051

  • CrossRef
  • Google Scholar

• 136

  WangHGuanJGuanLYangJWuKLinQet al. Further Evidence for "Gain-of-Function" Mechanism of DFNA5 Related Hearing Loss. Sci Rep (2018) 8:18424. doi: 10.1038/s41598-018-26554-7

  • CrossRef
  • Google Scholar

• 137

  YuanYLiQSuYLinQGaoXLiuHet al. Comprehensive Genetic Testing of Chinese SNHL Patients and Variants Interpretation Using ACMG Guidelines and Ethnically Matched Normal Controls. Eur J Hum Genet (2020) 28:2231–43. doi: 10.1038/s41431-019-0510-6

  • CrossRef
  • Google Scholar

• 138

  KerseyPJAllenJEAllotABarbaMBodduSBoltBJet al. Ensembl Genomes 2018: An Integrated Omics Infrastructure for Non-Vertebrate Species. Nucleic Acids Res (2018) 46:D1D802–D8. doi: 10.1093/nar/gkx1011

  • CrossRef
  • Google Scholar

• 139

  ZerbinoDRAchuthanPAkanniWAmodeMRBarrellDBhaiJet al. Ensembl 2018. Nucleic Acids Res (2018) 46:D1D754–D61. doi: 10.1093/nar/gkx1098

  • CrossRef
  • Google Scholar

• 140

  Op de BeeckKVan CampGThysSCoolsNCallebautIVrijensKet al. The DFNA5 Gene, Responsible for Hearing Loss and Involved in Cancer, Encodes a Novel Apoptosis-Inducing Protein. Eur J Hum Genet (2011) 19:9965–73. doi: 10.1038/ejhg.2011.63

  • CrossRef
  • Google Scholar

• 141

  GalluzziLVitaleIAaronsonSAAbramsJMAdamDAgostinisPet al. Molecular Mechanisms of Cell Death: Recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ (2018) 25:3486–541. doi: 10.1038/s41418-017-0012-4

  • CrossRef
  • Google Scholar

• 142

  NagataSTanakaM. Programmed Cell Death and the Immune System. Nat Rev Immunol (2017) 17:5333–40. doi: 10.1038/nri.2016.153

  • CrossRef
  • Google Scholar

• 143

  AizawaEKarasawaTWatanabeSKomadaTKimuraHKamataRet al. GSDME-Dependent Incomplete Pyroptosis Permits Selective IL-1alpha Release Under Caspase-1 Inhibition. iScience (2020) 23:5101070. doi: 10.1016/j.isci.2020.101070

  • CrossRef
  • Google Scholar

• 144

  WangCYangTXiaoJXuCAlippeYSunKet al. NLRP3 Inflammasome Activation Triggers Gasdermin D-Independent Inflammation. Sci Immunol (2021) 6:64:eabj3859. doi: 10.1126/sciimmunol.abj3859

  • CrossRef
  • Google Scholar

• 145

  CollinRWKalayEOostrikJCaylanRWollnikBArslanSet al. Involvement of DFNB59 Mutations in Autosomal Recessive Nonsyndromic Hearing Impairment. Hum Mutat (2007) 28:7718–23. doi: 10.1002/humu.20510

  • CrossRef
  • Google Scholar

• 146

  MujtabaGBukhariIFatimaANazS. A P.C343S Missense Mutation in PJVK Causes Progressive Hearing Loss. Gene (2012) 504:198–01. doi: 10.1016/j.gene.2012.05.013

  • CrossRef
  • Google Scholar

• 147

  ZhengZDengWLouXBaiYWangJZengHet al. Gasdermins: Pore-Forming Activities and Beyond. Acta Biochim Biophys Sin (Shanghai) (2020) 52:5467–74. doi: 10.1093/abbs/gmaa016

  • CrossRef
  • Google Scholar

• 148

  DelmaghaniSDefournyJAghaieABeurgMDulonDThelenNet al. Hypervulnerability to Sound Exposure Through Impaired Adaptive Proliferation of Peroxisomes. Cell (2015) 163:4894–906. doi: 10.1016/j.cell.2015.10.023

  • CrossRef
  • Google Scholar

• 149

  KazmierczakMKazmierczakPPengAWHarrisSLShahPPuelJLet al. Pejvakin, a Candidate Stereociliary Rootlet Protein, Regulates Hair Cell Function in a Cell-Autonomous Manner. J Neurosci (2017) 37:133447–64. doi: 10.1523/JNEUROSCI.2711-16.2017

  • CrossRef
  • Google Scholar

• 150

  Vande WalleLLamkanfiM. Pyroptosis. Curr Biol (2016) 26:13R568–R72. doi: 10.1016/j.cub.2016.02.019

  • CrossRef
  • Google Scholar

• 151

  JorgensenIMiaoEA. Pyroptotic Cell Death Defends Against Intracellular Pathogens. Immunol Rev (2015) 265:1130–42. doi: 10.1111/imr.12287

  • CrossRef
  • Google Scholar

• 152

  MonackDMRaupachBHromockyjAEFalkowS. Salmonella Typhimurium Invasion Induces Apoptosis in Infected Macrophages. Proc Natl Acad Sci U S A (1996) 93:189833–8. doi: 10.1073/pnas.93.18.9833

  • CrossRef
  • Google Scholar

• 153

  ChenYSmithMRThirumalaiKZychlinskyA. A Bacterial Invasin Induces Macrophage Apoptosis by Binding Directly to ICE. EMBO J (1996) 15:153853–60. doi: 10.1002/j.1460-2075.1996.tb00759.x

  • CrossRef
  • Google Scholar

• 154

  HershDMonackDMSmithMRGhoriNFalkowSZychlinskyA. The Salmonella Invasin SipB Induces Macrophage Apoptosis by Binding to Caspase-1. Proc Natl Acad Sci USA (1999) 96:52396–401. doi: 10.1073/pnas.96.5.2396

  • CrossRef
  • Google Scholar

• 155

  JorgensenIZhangYKrantzBAMiaoEA. Pyroptosis Triggers Pore-Induced Intracellular Traps (PITs) That Capture Bacteria and Lead to Their Clearance by Efferocytosis. J Exp Med (2016) 213:102113–28. doi: 10.1084/jem.20151613

  • CrossRef
  • Google Scholar

• 156

  ChenXHeWTHuLLiJFangYWangXet al. Pyroptosis Is Driven by Non-Selective Gasdermin-D Pore and its Morphology is Different From MLKL Channel-Mediated Necroptosis. Cell Res (2016) 26:91007–20. doi: 10.1038/cr.2016.100

  • CrossRef
  • Google Scholar

• 157

  KovacsSBMiaoEA. Gasdermins: Effectors of Pyroptosis. Trends Cell Biol (2017) 27:9673–84. doi: 10.1016/j.tcb.2017.05.005

  • CrossRef
  • Google Scholar

• 158

  DavisMAFairgrieveMRDen HartighAYakovenkoODuvvuriBLoodCet al. Calpain Drives Pyroptotic Vimentin Cleavage, Intermediate Filament Loss, and Cell Rupture That Mediates Immunostimulation. Proc Natl Acad Sci U S A (2019) 116:115061–70. doi: 10.1073/pnas.1818598116

  • CrossRef
  • Google Scholar

• 159

  AnderssonUTraceyKJ. HMGB1 Is a Therapeutic Target for Sterile Inflammation and Infection. Annu Rev Immunol (2011) 29:139–62. doi: 10.1146/annurev-immunol-030409-101323

  • CrossRef
  • Google Scholar

• 160

  BroderickSWangXSimmsNPage-McCawA. Drosophila Ninjurin A Induces Nonapoptotic Cell Death. PLoS One (2012) 7:9:e44567. doi: 10.1371/journal.pone.0044567

  • CrossRef
  • Google Scholar

• 161

  HuJJLiuXXiaSZhangZZhangYZhaoJet al. FDA-Approved Disulfiram Inhibits Pyroptosis by Blocking Gasdermin D Pore Formation. Nat Immunol (2020) 21:7736–45. doi: 10.1038/s41590-020-0669-6

  • CrossRef
  • Google Scholar

• 162

  HumphriesFShmuel-GaliaLKetelut-CarneiroNLiSWangBNemmaraVVet al. Succination Inactivates Gasdermin D and Blocks Pyroptosis. Science (2020) 369:65111633–7. doi: 10.1126/science.abb9818

  • CrossRef
  • Google Scholar

• 163

  Van OpdenboschNLamkanfiM. Caspases in Cell Death, Inflammation, and Disease. Immunity (2019) 50:61352–64. doi: 10.1016/j.immuni.2019.05.020

  • CrossRef
  • Google Scholar

• 164

  TsuchiyaK. Inflammasome-Associated Cell Death: Pyroptosis, Apoptosis, and Physiological Implications. Microbiol Immunol (2020) 64:4252–69. doi: 10.1111/1348-0421.12771

  • CrossRef
  • Google Scholar

• 165

  FinkSLCooksonBT. Caspase-1-Dependent Pore Formation During Pyroptosis Leads to Osmotic Lysis of Infected Host Macrophages. Cell Microbiol (2006) 8:111812–25. doi: 10.1111/j.1462-5822.2006.00751.x

  • CrossRef
  • Google Scholar

• 166

  RalstonKSPetriWA. The Ways of a Killer: How Does Entamoeba histolytica Elicit Host Cell Death? Essays Biochem (2011) 51:193–210. doi: 10.1042/bse0510193

  • CrossRef
  • Google Scholar

• 167

  RavdinJISperelakisNGuerrantRL. Effect of Ion Channel Inhibitors on the Cytopathogenicity of Entamoeba histolytica. J Infect Dis (1982) 146:3335–40. doi: 10.1093/infdis/146.3.335

  • CrossRef
  • Google Scholar

• 168

  HustonCDHouptERMannBJHahnCSPetriWAJr. Caspase 3-Dependent Killing of Host Cells by the Parasite Entamoeba histolytica. Cell Microbiol (2000) 2:6617–25. doi: 10.1046/j.1462-5822.2000.00085.x

  • CrossRef
  • Google Scholar

• 169

  BeckerSMChoKNGuoXFendigKOosmanMNWhiteheadRet al. Epithelial Cell Apoptosis Facilitates Entamoeba histolytica Infection in the Gut. Am J Pathol (2010) 176:31316–22. doi: 10.2353/ajpath.2010.090740

  • CrossRef
  • Google Scholar

• 170

  MascarenhasDPACerqueiraDMPereiraMSFCastanheiraFVSFernandesTDManinGZet al. Inhibition of Caspase-1 or Gasdermin-D Enable Caspase-8 Activation in the Naip5/NLRC4/ASC Inflammasome. PLoS Pathog (2017) 13:8:e1006502. doi: 10.1371/journal.ppat.1006502

  • CrossRef
  • Google Scholar

• 171

  Van OpdenboschNVan GorpHVerdoncktMSaavedraPHVde VasconcelosNMGoncalvesAet al. Caspase-1 Engagement and TLR-Induced C-FLIP Expression Suppress ASC/caspase-8-Dependent Apoptosis by Inflammasome Sensors NLRP1b and NLRC4. Cell Rep (2017) 21:123427–44. doi: 10.1016/j.celrep.2017.11.088

  • CrossRef
  • Google Scholar

• 172

  AkhterAGavrilinMAFrantzLWashingtonSDittyCLimoliDet al. Caspase-7 Activation by the Nlrc4/Ipaf Inflammasome Restricts Legionella Pneumophila Infection. PLoS Pathog (2009) 5:4:e1000361. doi: 10.1371/journal.ppat.1000361

  • CrossRef
  • Google Scholar

• 173

  ErenerSPetrilliVKassnerIMinottiRCastilloRSantoroRet al. Inflammasome-Activated Caspase 7 Cleaves PARP1 to Enhance the Expression of a Subset of NF-kappaB Target Genes. Mol Cell (2012) 46:2200–11. doi: 10.1016/j.molcel.2012.02.016

  • CrossRef
  • Google Scholar

• 174

  KangSJWangSKuidaKYuanJ. Distinct Downstream Pathways of Caspase-11 in Regulating Apoptosis and Cytokine Maturation During Septic Shock Response. Cell Death Differ (2002) 9:101115–25. doi: 10.1038/sj.cdd.4401087

  • CrossRef
  • Google Scholar

• 175

  SagulenkoVVitakNVajjhalaPRVinceJEStaceyKJ. Caspase-1 is an Apical Caspase Leading to Caspase-3 Cleavage in the AIM2 Inflammasome Response, Independent of Caspase-8. J Mol Biol (2018) 430:2238–47. doi: 10.1016/j.jmb.2017.10.028

  • CrossRef
  • Google Scholar

• 176

  AkinoKToyotaMSuzukiHImaiTMaruyamaRKusanoMet al. Identification of DFNA5 as a Target of Epigenetic Inactivation in Gastric Cancer. Cancer Sci (2007) 98:188–95. doi: 10.1111/j.1349-7006.2006.00351.x

  • CrossRef
  • Google Scholar

• 177

  KimMSLebronCNagpalJKChaeYKChangXHuangYet al. Methylation of the DFNA5 Increases Risk of Lymph Node Metastasis in Human Breast Cancer. Biochem Biophys Res Commun (2008) 370:138–43. doi: 10.1016/j.bbrc.2008.03.026

  • CrossRef
  • Google Scholar

• 178

  KimMSChangXYamashitaKNagpalJKBaekJHWuGet al. Aberrant Promoter Methylation and Tumor Suppressive Activity of the DFNA5 Gene in Colorectal Carcinoma. Oncogene (2008) 27:253624–34. doi: 10.1038/sj.onc.1211021

  • CrossRef
  • Google Scholar

• 179

  BladerIJColemanBIChenCTGubbelsMJ. Lytic Cycle of Toxoplasma gondii: 15 Years Later. Annu Rev Microbiol (2015) 69:463–85. doi: 10.1146/annurev-micro-091014-104100

  • CrossRef
  • Google Scholar

• 180

  HuRSHeJJElsheikhaHMZouYEhsanMMaQNet al. Transcriptomic Profiling of Mouse Brain During Acute and Chronic Infections by Toxoplasma gondii Oocysts. Front Microbiol (2020) 11:570903. doi: 10.3389/fmicb.2020.570903

  • CrossRef
  • Google Scholar

• 181

  ChannonJYMiselisKAMinnsLADuttaCKasperLH. Toxoplasma gondii Induces Granulocyte Colony-Stimulating Factor and Granulocyte-Macrophage Colony-Stimulating Factor Secretion by Human Fibroblasts: Implications for Neutrophil Apoptosis. Infect Immun (2002) 70:116048–57. doi: 10.1128/IAI.70.11.6048-6057.2002

  • CrossRef
  • Google Scholar

• 182

  AgaEKatschinskiDMvan ZandbergenGLaufsHHansenBMullerKet al. Inhibition of the Spontaneous Apoptosis of Neutrophil Granulocytes by the Intracellular Parasite Leishmania Major. J Immunol (2002) 169:2898–905. doi: 10.4049/jimmunol.169.2.898

  • CrossRef
  • Google Scholar

• 183

  van ZandbergenGKlingerMMuellerADannenbergSGebertASolbachWet al. Cutting Edge: Neutrophil Granulocyte Serves as a Vector for Leishmania Entry Into Macrophages. J Immunol (2004) 173:116521–5. doi: 10.4049/jimmunol.173.11.6521

  • CrossRef
  • Google Scholar

• 184

  ConosSALawlorKEVauxDLVinceJELindqvistLM. Cell Death is Not Essential for Caspase-1-Mediated Interleukin-1beta Activation and Secretion. Cell Death Differ (2016) 23:111827–38. doi: 10.1038/cdd.2016.69

  • CrossRef
  • Google Scholar

• 185

  ChenKWGrossCJSotomayorFVStaceyKJTschoppJSweetMJet al. The Neutrophil NLRC4 Inflammasome Selectively Promotes IL-1beta Maturation Without Pyroptosis During Acute Salmonella Challenge. Cell Rep (2014) 8:2570–82. doi: 10.1016/j.celrep.2014.06.028

  • CrossRef
  • Google Scholar

• 186

  BroughDRothwellNJ. Caspase-1-Dependent Processing of Pro-Interleukin-1beta is Cytosolic and Precedes Cell Death. J Cell Sci (2007) 120:Pt 5772–81. doi: 10.1242/jcs.03377

  • CrossRef
  • Google Scholar

• 187

  GaidtMMEbertTSChauhanDSchmidtTSchmid-BurgkJLRapinoFet al. Human Monocytes Engage an Alternative Inflammasome Pathway. Immunity (2016) 44:4833–46. doi: 10.1016/j.immuni.2016.01.012

  • CrossRef
  • Google Scholar

• 188

  Martin-SanchezFDiamondCZeitlerMGomezAIBaroja-MazoABagnallJet al. Inflammasome-Dependent IL-1beta Release Depends Upon Membrane Permeabilisation. Cell Death Differ (2016) 23:71219–31. doi: 10.1038/cdd.2015.176

  • CrossRef
  • Google Scholar

• 189

  RussoHMRathkeyJBoyd-TresslerAKatsnelsonMAAbbottDWDubyakGR. Active Caspase-1 Induces Plasma Membrane Pores That Precede Pyroptotic Lysis and are Blocked by Lanthanides. J Immunol (2016) 197:41353–67. doi: 10.4049/jimmunol.1600699

  • CrossRef
  • Google Scholar

• 190

  MonteleoneMStanleyACChenKWBrownDLBezbradicaJSvon PeinJBet al. Interleukin-1beta Maturation Triggers its Relocation to the Plasma Membrane for Gasdermin-D-Dependent and -Independent Secretion. Cell Rep (2018) 24:61425–33. doi: 10.1016/j.celrep.2018.07.027

  • CrossRef
  • Google Scholar

• 191

  CerrettiDPKozloskyCJMosleyBNelsonNVan NessKGreenstreetTAet al. Molecular Cloning of the Interleukin-1 Beta Converting Enzyme. Science (1992) 256:505397–100. doi: 10.1126/science.1373520

  • CrossRef
  • Google Scholar

• 192

  GarlandaCDinarelloCAMantovaniA. The Interleukin-1 Family: Back to the Future. Immunity (2013) 39:61003–18. doi: 10.1016/j.immuni.2013.11.010

  • CrossRef
  • Google Scholar

• 193

  SnyderJSSoumierABrewerMPickelJCameronHA. Adult Hippocampal Neurogenesis Buffers Stress Responses and Depressive Behaviour. Nature (2011) 476:7361458–61. doi: 10.1038/nature10287

  • CrossRef
  • Google Scholar

• 194

  NickelWRabouilleC. Mechanisms of Regulated Unconventional Protein Secretion. Nat Rev Mol Cell Biol (2009) 10:2148–55. doi: 10.1038/nrm2617

  • CrossRef
  • Google Scholar

• 195

  RabouilleCMalhotraVNickelW. Diversity in Unconventional Protein Secretion. J Cell Sci (2012) 125:Pt 225251–5. doi: 10.1242/jcs.103630

  • CrossRef
  • Google Scholar

• 196

  EvavoldCLRuanJTanYXiaSWuHKaganJC. The Pore-Forming Protein Gasdermin D Regulates Interleukin-1 Secretion From Living Macrophages. Immunity (2018) 48:135–44.e6. doi: 10.1016/j.immuni.2017.11.013

  • CrossRef
  • Google Scholar

• 197

  ZanoniITanYDi GioiaMSpringsteadJRKaganJC. By Capturing Inflammatory Lipids Released From Dying Cells, the Receptor CD14 Induces Inflammasome-Dependent Phagocyte Hyperactivation. Immunity (2017) 47:4697–709.e3. doi: 10.1016/j.immuni.2017.09.010

  • CrossRef
  • Google Scholar

• 198

  RuhlSShkarinaKDemarcoBHeiligRSantosJCBrozP. ESCRT-Dependent Membrane Repair Negatively Regulates Pyroptosis Downstream of GSDMD Activation. Science (2018) 362:6417956–60. doi: 10.1126/science.aar7607

  • CrossRef
  • Google Scholar

• 199

  AndrewsNWAlmeidaPECorrotteM. Damage Control: Cellular Mechanisms of Plasma Membrane Repair. Trends Cell Biol (2014) 24:12734–42. doi: 10.1016/j.tcb.2014.07.008

  • CrossRef
  • Google Scholar

• 200

  BilodeauPSUrbanowskiJLWinistorferSCPiperRC. The Vps27p Hse1p Complex Binds Ubiquitin and Mediates Endosomal Protein Sorting. Nat Cell Biol (2002) 4:7534–9. doi: 10.1038/ncb815

  • CrossRef
  • Google Scholar

• 201

  KeefeDShiLFeskeSMassolRNavarroFKirchhausenTet al. Perforin Triggers a Plasma Membrane-Repair Response That Facilitates CTL Induction of Apoptosis. Immunity (2005) 23:3249–62. doi: 10.1016/j.immuni.2005.08.001

  • CrossRef
  • Google Scholar

• 202

  JimenezAJMaiuriPLafaurie-JanvoreJDivouxSPielMPerezF. ESCRT Machinery is Required for Plasma Membrane Repair. Science (2014) 343:61741247136. doi: 10.1126/science.1247136

  • CrossRef
  • Google Scholar

• 203

  SchefferLLSreetamaSCSharmaNMedikayalaSBrownKJDefourAet al. Mechanism of Ca(2)(+)-Triggered ESCRT Assembly and Regulation of Cell Membrane Repair. Nat Commun (2014) 5:5646. doi: 10.1038/ncomms6646

  • CrossRef
  • Google Scholar

• 204

  McNeilPLKirchhausenT. An Emergency Response Team for Membrane Repair. Nat Rev Mol Cell Biol (2005) 6:6499–505. doi: 10.1038/nrm1665

  • CrossRef
  • Google Scholar

• 205

  WalevIBhakdiSCHofmannFDjonderNValevaAAktoriesKet al. Delivery of Proteins Into Living Cells by Reversible Membrane Permeabilization With Streptolysin-O. Proc Natl Acad Sci U S A (2001) 98:63185–90. doi: 10.1073/pnas.051429498

  • CrossRef
  • Google Scholar

• 206

  TamCIdoneVDevlinCFernandesMCFlanneryAHeXet al. Exocytosis of Acid Sphingomyelinase by Wounded Cells Promotes Endocytosis and Plasma Membrane Repair. J Cell Biol (2010) 189:61027–38. doi: 10.1083/jcb.201003053

  • CrossRef
  • Google Scholar

• 207

  IdoneVTamCGossJWToomreDPypaertMAndrewsNW. Repair of Injured Plasma Membrane by Rapid Ca2+-Dependent Endocytosis. J Cell Biol (2008) 180:5905–14. doi: 10.1083/jcb.200708010

  • CrossRef
  • Google Scholar

• 208

  HolopainenJMMedinaOPMetsoAJKinnunenPK. Sphingomyelinase Activity Associated With Human Plasma Low Density Lipoprotein. J Biol Chem (2000) 275:2216484–9. doi: 10.1074/jbc.275.22.16484

  • CrossRef
  • Google Scholar

• 209

  GulbinsEKolesnickR. Raft Ceramide in Molecular Medicine. Oncogene (2003) 22:457070–7. doi: 10.1038/sj.onc.1207146

  • CrossRef
  • Google Scholar

• 210

  Ramirez-MontielFMendoza-MaciasCAndrade-GuillenSRangel-SerranoAParamo-PerezIRivera-CuellarPEet al. Plasma Membrane Damage Repair is Mediated by an Acid Sphingomyelinase in Entamoeba histolytica. PLoS Pathog (2019) 15:8:e1008016. doi: 10.1371/journal.ppat.1008016

  • CrossRef
  • Google Scholar

• 211

  MiaoEALeafIATreutingPMMaoDPDorsMSarkarAet al. Caspase-1-Induced Pyroptosis is an Innate Immune Effector Mechanism Against Intracellular Bacteria. Nat Immunol (2010) 11:121136–42. doi: 10.1038/ni.1960

  • CrossRef
  • Google Scholar

• 212

  YuJNagasuHMurakamiTHoangHBroderickLHoffmanHMet al. Inflammasome Activation Leads to Caspase-1-Dependent Mitochondrial Damage and Block of Mitophagy. Proc Natl Acad Sci U S A (2014) 111:4315514–9. doi: 10.1073/pnas.1414859111

  • CrossRef
  • Google Scholar

• 213

  Rivers-AutyJBroughD. Potassium Efflux Fires the Canon: Potassium Efflux as a Common Trigger for Canonical and Noncanonical NLRP3 Pathways. Eur J Immunol (2015) 45:102758–61. doi: 10.1002/eji.201545958

  • CrossRef
  • Google Scholar

• 214

  Schmid-BurgkJLGaidtMMSchmidtTEbertTSBartokEHornungV. Caspase-4 Mediates non-Canonical Activation of the NLRP3 Inflammasome in Human Myeloid Cells. Eur J Immunol (2015) 45:102911–7. doi: 10.1002/eji.201545523

  • CrossRef
  • Google Scholar

• 215

  RuhlSBrozP. Caspase-11 Activates a Canonical NLRP3 Inflammasome by Promoting K(+) Efflux. Eur J Immunol (2015) 45:102927–36. doi: 10.1002/eji.201545772

  • CrossRef
  • Google Scholar

• 216

  PlatnichJMChungHLauASandallCFBondzi-SimpsonAChenHMet al. Shiga Toxin/Lipopolysaccharide Activates Caspase-4 and Gasdermin D to Trigger Mitochondrial Reactive Oxygen Species Upstream of the NLRP3 Inflammasome. Cell Rep (2018) 25:61525–36.e7. doi: 10.1016/j.celrep.2018.09.071

  • CrossRef
  • Google Scholar

• 217

  MarieCVerkerkeHPTheodorescuDPetriWA. A Whole-Genome RNAi Screen Uncovers a Novel Role for Human Potassium Channels in Cell Killing by the Parasite Entamoeba histolytica. Sci Rep (2015) 5:13613. doi: 10.1038/srep13613

  • CrossRef
  • Google Scholar

• 218

  RomaEHMacedoJPGoesGRGoncalvesJLCastroWCisalpinoDet al. Impact of Reactive Oxygen Species (ROS) on the Control of Parasite Loads and Inflammation in Leishmania Amazonensis Infection. Parasit Vectors (2016) 9:193. doi: 10.1186/s13071-016-1472-y

  • CrossRef
  • Google Scholar

• 219

  CardoniRLAntunezMIMoralesCNantesIR. Release of Reactive Oxygen Species by Phagocytic Cells in Response to Live Parasites in Mice Infected With Trypanosoma cruzi. Am J Trop Med Hyg (1997) 56:3329–34. doi: 10.4269/ajtmh.1997.56.329

  • CrossRef
  • Google Scholar

• 220

  CardoniRLRottenbergMESeguraEL. Increased Production of Reactive Oxygen Species by Cells From Mice Acutely Infected With Trypanosoma cruzi. Cell Immunol (1990) 128:111–21. doi: 10.1016/0008-8749(90)90002-9

  • CrossRef
  • Google Scholar

• 221

  PiacenzaLAlvarezMNPeluffoGRadiR. Fighting the Oxidative Assault: The Trypanosoma cruzi Journey to Infection. Curr Opin Microbiol (2009) 12:4415–21. doi: 10.1016/j.mib.2009.06.011

  • CrossRef
  • Google Scholar

• 222

  PineyroMDArcariTRobelloCRadiRTrujilloM. Tryparedoxin Peroxidases From Trypanosoma cruzi: High Efficiency in the Catalytic Elimination of Hydrogen Peroxide and Peroxynitrite. Arch Biochem Biophys (2011) 507:2287–95. doi: 10.1016/j.abb.2010.12.014

  • CrossRef
  • Google Scholar

• 223

  AlvarezMNPeluffoGPiacenzaLRadiR. Intraphagosomal Peroxynitrite as a Macrophage-Derived Cytotoxin Against Internalized Trypanosoma cruzi: Consequences for Oxidative Killing and Role of Microbial Peroxiredoxins in Infectivity. J Biol Chem (2011) 286:86627–40. doi: 10.1074/jbc.M110.167247

  • CrossRef
  • Google Scholar

• 224

  Higuchi MdeLBenvenutiLAMartins ReisMMetzgerM. Pathophysiology of the Heart in Chagas' Disease: Current Status and New Developments. Cardiovasc Res (2003) 60:196–07. doi: 10.1016/s0008-6363(03)00361-4

  • CrossRef
  • Google Scholar

• 225

  NagajyothiFMachadoFSBurleighBAJelicksLASchererPEMukherjeeSet al. Mechanisms of Trypanosoma cruzi Persistence in Chagas Disease. Cell Microbiol (2012) 14:5634–43. doi: 10.1111/j.1462-5822.2012.01764.x

  • CrossRef
  • Google Scholar

• 226

  TanowitzHBMachadoFSJelicksLAShiraniJde CarvalhoACSprayDCet al. Perspectives on Trypanosoma cruzi-Induced Heart Disease (Chagas Disease). Prog Cardiovasc Dis (2009) 51:6524–39. doi: 10.1016/j.pcad.2009.02.001

  • CrossRef
  • Google Scholar

• 227

  TanowitzHBWeissLMMontgomerySP. Chagas Disease has Now Gone Global. PloS Negl Trop Dis (2011) 5:4:e1136. doi: 10.1371/journal.pntd.0001136

  • CrossRef
  • Google Scholar

• 228

  MachadoFSTylerKMBrantFEsperLTeixeiraMMTanowitzHB. Pathogenesis of Chagas Disease: Time to Move on. Front Biosci (Elite Ed) (2012) 4:1743–58. doi: 10.2741/495

  • CrossRef
  • Google Scholar

• 229

  MachadoFSDutraWOEsperLGollobKJTeixeiraMMFactorSMet al. Current Understanding of Immunity to Trypanosoma cruzi Infection and Pathogenesis of Chagas Disease. Semin Immunopathol (2012) 34:6753–70. doi: 10.1007/s00281-012-0351-7

  • CrossRef
  • Google Scholar

• 230

  SilvaGKCostaRSSilveiraTNCaetanoBCHortaCVGutierrezFRet al. Apoptosis-Associated Speck-Like Protein Containing a Caspase Recruitment Domain Inflammasomes Mediate IL-1beta Response and Host Resistance to Trypanosoma cruzi Infection. J Immunol (2013) 191:63373–83. doi: 10.4049/jimmunol.1203293

  • CrossRef
  • Google Scholar

• 231

  GoncalvesVMMatteucciKCBuzzoCLMiolloBHFerranteDTorrecilhasACet al. NLRP3 Controls Trypanosoma cruzi Infection Through a Caspase-1-Dependent IL-1R-Independent NO Production. PloS Negl Trop Dis (2013) 7:10:e2469. doi: 10.1371/journal.pntd.0002469

  • CrossRef
  • Google Scholar

• 232

  DereticVSaitohTAkiraS. Autophagy in Infection, Inflammation and Immunity. Nat Rev Immunol (2013) 13:10722–37. doi: 10.1038/nri3532

  • CrossRef
  • Google Scholar

• 233

  YuPWangHYTianMLiAXChenXSWangXLet al. Eukaryotic Elongation Factor-2 Kinase Regulates the Cross-Talk Between Autophagy and Pyroptosis in Doxorubicin-Treated Human Melanoma Cells In Vitro. Acta Pharmacol Sin (2019) 40:91237–44. doi: 10.1038/s41401-019-0222-z

  • CrossRef
  • Google Scholar

• 234

  ShioMTEisenbarthSCSavariaMVinetAFBellemareMJHarderKWet al. Malarial Hemozoin Activates the NLRP3 Inflammasome Through Lyn and Syk Kinases. PLoS Pathog (2009) 5:8:e1000559. doi: 10.1371/journal.ppat.1000559

  • CrossRef
  • Google Scholar

• 235

  KalantariPDeOliveiraRBChanJCorbettYRathinamVStutzAet al. Dual Engagement of the NLRP3 and AIM2 Inflammasomes by Plasmodium-Derived Hemozoin and DNA During Malaria. Cell Rep (2014) 6:1196–210. doi: 10.1016/j.celrep.2013.12.014

  • CrossRef
  • Google Scholar

• 236

  PereiraLMNAssisPAde AraujoNMDursoDFJunqueiraCAtaideMAet al. Caspase-8 Mediates Inflammation and Disease in Rodent Malaria. Nat Commun (2020) 11:14596. doi: 10.1038/s41467-020-18295-x

  • CrossRef
  • Google Scholar

• 237

  RauchIDeetsKAJiDXvon MoltkeJTenthoreyJLLeeAYet al. NAIP-NLRC4 Inflammasomes Coordinate Intestinal Epithelial Cell Expulsion With Eicosanoid and IL-18 Release via Activation of Caspase-1 and -8. Immunity (2017) 46:4649–59. doi: 10.1016/j.immuni.2017.03.016

  • CrossRef
  • Google Scholar

• 238

  CorreaGMarques da SilvaCde Abreu Moreira-SouzaACVommaroRCCoutinho-SilvaR. Activation of the P2X(7) Receptor Triggers the Elimination of Toxoplasma gondii Tachyzoites From Infected Macrophages. Microbes Infect (2010) 12:6497–504. doi: 10.1016/j.micinf.2010.03.004

  • CrossRef
  • Google Scholar

• 239

  DeLaneyAABerryCTChristianDAHartABjanesEWynosky-DolfiMAet al. Caspase-8 Promotes C-Rel-Dependent Inflammatory Cytokine Expression and Resistance Against Toxoplasma gondii. Proc Natl Acad Sci USA (2019) 116:2411926–35. doi: 10.1073/pnas.1820529116

  • CrossRef
  • Google Scholar

• 240

  VinceJESilkeJ. The Intersection of Cell Death and Inflammasome Activation. Cell Mol Life Sci (2016) 73:11–122349-67. doi: 10.1007/s00018-016-2205-2

  • CrossRef
  • Google Scholar

• 241

  BatistaSJStillKMJohansonDThompsonJAO'BrienCALukensJRet al. Gasdermin-D-Dependent IL-1alpha Release From Microglia Promotes Protective Immunity During Chronic Toxoplasma gondii Infection. Nat Commun (2020) 11:13687. doi: 10.1038/s41467-020-17491-z

  • CrossRef
  • Google Scholar

• 242

  Lima-JuniorDSCostaDLCarregaroVCunhaLDSilvaALMineoTWet al. Inflammasome-Derived IL-1beta Production Induces Nitric Oxide-Mediated Resistance to Leishmania. Nat Med (2013) 19:7909–15. doi: 10.1038/nm.3221

  • CrossRef
  • Google Scholar

• 243

  Lima-JuniorDSMineoTWPCalichVLGZamboniDS. Dectin-1 Activation During Leishmania Amazonensis Phagocytosis Prompts Syk-Dependent Reactive Oxygen Species Production to Trigger Inflammasome Assembly and Restriction of Parasite Replication. J Immunol (2017) 199:62055–68. doi: 10.4049/jimmunol.1700258

  • CrossRef
  • Google Scholar

• 244

  de CarvalhoRVHAndradeWALima-JuniorDSDiluccaMde OliveiraCVWangKet al. Leishmania Lipophosphoglycan Triggers Caspase-11 and the non-Canonical Activation of the NLRP3 Inflammasome. Cell Rep (2019) 26:2429–37.e5. doi: 10.1016/j.celrep.2018.12.047

  • CrossRef
  • Google Scholar

• 245

  Farias LuzNBalajiSOkudaKBarretoASBertinJGoughPJet al. RIPK1 and PGAM5 Control Leishmania Replication Through Distinct Mechanisms. J Immunol (2016) 196:125056–63. doi: 10.4049/jimmunol.1502492

  • CrossRef
  • Google Scholar

• 246

  EskelinenELKovacsAL. Double Membranes vs. Lipid Bilayers, and Their Significance for Correct Identification of Macroautophagic Structures. Autophagy (2011) 7:9931–2. doi: 10.4161/auto.7.9.16679

  • CrossRef
  • Google Scholar

• 247

  PandayASahooMKOsorioDBatraS. NADPH Oxidases: An Overview From Structure to Innate Immunity-Associated Pathologies. Cell Mol Immunol (2015) 12:15–23. doi: 10.1038/cmi.2014.89

  • CrossRef
  • Google Scholar

• 248

  DhimanMGargNJ. P47phox-/- Mice are Compromised in Expansion and Activation of CD8+ T Cells and Susceptible to Trypanosoma cruzi Infection. PLoS Pathog (2014) 10:12:e1004516. doi: 10.1371/journal.ppat.1004516

  • CrossRef
  • Google Scholar

• 249

  Cunha-NetoEDzauVJAllenPDStamatiouDBenvenuttiLHiguchiMLet al. Cardiac Gene Expression Profiling Provides Evidence for Cytokinopathy as a Molecular Mechanism in Chagas' Disease Cardiomyopathy. Am J Pathol (2005) 167:2305–13. doi: 10.1016/S0002-9440(10)62976-8

  • CrossRef
  • Google Scholar

• 250

  StarkeyJKobayashiNNumaguchiYMoritaniT. Cytotoxic Lesions of the Corpus Callosum That Show Restricted Diffusion: Mechanisms, Causes, and Manifestations. Radiographics (2017) 37:2562–76. doi: 10.1148/rg.2017160085

  • CrossRef
  • Google Scholar

• 251

  HeusslerVTKuenziPRottenbergS. Inhibition of Apoptosis by Intracellular Protozoan Parasites. Int J Parasitol (2001) 31:111166–76. doi: 10.1016/s0020-7519(01)00271-5

  • CrossRef
  • Google Scholar

• 252

  MatteucciKCPereiraGJSWeinlichRBortoluciKR. Frontline Science: Autophagy is a Cell Autonomous Effector Mechanism Mediated by NLRP3 to Control Trypanosoma cruzi Infection. J Leukoc Biol (2019) 106:3531–40. doi: 10.1002/JLB.HI1118-461R

  • CrossRef
  • Google Scholar

• 253

  LambCAYoshimoriTToozeSA. The Autophagosome: Origins Unknown, Biogenesis Complex. Nat Rev Mol Cell Biol (2013) 14:12759–74. doi: 10.1038/nrm3696

  • CrossRef
  • Google Scholar

• 254

  SeveauSTurnerJGavrilinMATorrellesJBHall-StoodleyLYountJSet al. Checks and Balances Between Autophagy and Inflammasomes During Infection. J Mol Biol (2018) 430:2174–92. doi: 10.1016/j.jmb.2017.11.006

  • CrossRef
  • Google Scholar

• 255

  SunQFanJBilliarTRScottMJ. Inflammasome and Autophagy Regulation - a Two-Way Street. Mol Med (2017) 23:188–95. doi: 10.2119/molmed.2017.00077

  • CrossRef
  • Google Scholar

• 256

  WangXLiHLiWXieJWangFPengXet al. The Role of Caspase-1/GSDMD-Mediated Pyroptosis in Taxol-Induced Cell Death and a Taxol-Resistant Phenotype in Nasopharyngeal Carcinoma Regulated by Autophagy. Cell Biol Toxicol (2020) 36:5437–57. doi: 10.1007/s10565-020-09514-8

  • CrossRef
  • Google Scholar

• 257

  Rojas MarquezJDAnaYBaigorriREStempinCCCerbanFM. Mammalian Target of Rapamycin Inhibition in Trypanosoma cruzi-Infected Macrophages Leads to an Intracellular Profile That is Detrimental for Infection. Front Immunol (2018) 9:313. doi: 10.3389/fimmu.2018.00313

  • CrossRef
  • Google Scholar

• 258

  ZhuoLChenXSunYWangYShiYBuLet al. Rapamycin Inhibited Pyroptosis and Reduced the Release of IL-1beta and IL-18 in the Septic Response. BioMed Res Int (2020) 2020:5960375. doi: 10.1155/2020/5960375

  • CrossRef
  • Google Scholar

• 259

  Sena-Dos-SantosCBraga-da-SilvaCMarquesDAzevedo Dos Santos PinheiroJRibeiro-Dos-SantosACavalcanteGC. Unraveling Cell Death Pathways During Malaria Infection: What do We Know So Far? Cells (2021) 10:2. doi: 10.3390/cells10020479

  • CrossRef
  • Google Scholar

• 260

  KitchenADChiodiniPL. Malaria and Blood Transfusion. Vox Sang. (2006) 90:277–84. doi: 10.1111/j.1423-0410.2006.00733.x

  • CrossRef
  • Google Scholar

• 261

  PoespoprodjoJRFobiaWKenangalemEHasanuddinASugiartoPTjitraEet al. Highly Effective Therapy for Maternal Malaria Associated With a Lower Risk of Vertical Transmission. J Infect Dis (2011) 204:101613–9. doi: 10.1093/infdis/jir558

  • CrossRef
  • Google Scholar

• 262

  GazzinelliRTKalantariPFitzgeraldKAGolenbockDT. Innate Sensing of Malaria Parasites. Nat Rev Immunol (2014) 14:11744–57. doi: 10.1038/nri3742

  • CrossRef
  • Google Scholar

• 263

  MillerLHAckermanHCSuXZWellemsTE. Malaria Biology and Disease Pathogenesis: Insights for New Treatments. Nat Med (2013) 19:2156–67. doi: 10.1038/nm.3073

  • CrossRef
  • Google Scholar

• 264

  de CarvalhoRVHSoaresSMAGualbertoACMEvangelistaGCMDuqueJAMFerreiraAPet al. Plasmodium Berghei ANKA Infection Results in Exacerbated Immune Responses From C57BL/6 Mice Displaying Hypothalamic Obesity. Cytokine (2015) 76:2545–8. doi: 10.1016/j.cyto.2015.01.025

  • CrossRef
  • Google Scholar

• 265

  CobanCIshiiKJKawaiTHemmiHSatoSUematsuSet al. Toll-Like Receptor 9 Mediates Innate Immune Activation by the Malaria Pigment Hemozoin. J Exp Med (2005) 201:119–25. doi: 10.1084/jem.20041836

  • CrossRef
  • Google Scholar

• 266

  DeySBinduSGoyalMPalCAlamAIqbalMSet al. Impact of Intravascular Hemolysis in Malaria on Liver Dysfunction: Involvement of Hepatic Free Heme Overload, NF-kappaB Activation, and Neutrophil Infiltration. J Biol Chem (2012) 287:3226630–46. doi: 10.1074/jbc.M112.341255

  • CrossRef
  • Google Scholar

• 267

  PamplonaAFerreiraABallaJJeneyVBallaGEpiphanioSet al. Heme Oxygenase-1 and Carbon Monoxide Suppress the Pathogenesis of Experimental Cerebral Malaria. Nat Med (2007) 13:6703–10. doi: 10.1038/nm1586

  • CrossRef
  • Google Scholar

• 268

  FernandezPLDutraFFAlvesLFigueiredoRTMourao-SaDFortesGBet al. Heme Amplifies the Innate Immune Response to Microbial Molecules Through Spleen Tyrosine Kinase (Syk)-Dependent Reactive Oxygen Species Generation. J Biol Chem (2010) 285:4332844–51. doi: 10.1074/jbc.M110.146076

  • CrossRef
  • Google Scholar

• 269

  FongKYWrightDW. Hemozoin and Antimalarial Drug Discovery. Future Med Chem (2013) 5:121437–50. doi: 10.4155/fmc.13.113

  • CrossRef
  • Google Scholar

• 270

  DostertCGuardaGRomeroJFMenuPGrossOTardivelAet al. Malarial Hemozoin Is a Nalp3 Inflammasome Activating Danger Signal. PLoS One (2009) 4:8e6510. doi: 10.1371/journal.pone.0006510

  • CrossRef
  • Google Scholar

• 271

  DutraFFAlvesLSRodriguesDFernandezPLde OliveiraRBGolenbockDTet al. Hemolysis-Induced Lethality Involves Inflammasome Activation by Heme. Proc Natl Acad Sci USA (2014) 111:39:E4110–8. doi: 10.1073/pnas.1405023111

  • CrossRef
  • Google Scholar

• 272

  FlegrJPrandotaJSovickovaMIsrailiZH. Toxoplasmosis–a Global Threat. Correlation of Latent Toxoplasmosis With Specific Disease Burden in a Set of 88 Countries. PLoS One (2014) 9:3:e90203. doi: 10.1371/journal.pone.0090203

  • CrossRef
  • Google Scholar

• 273

  TyebjiSSeizovaSHannanAJTonkinCJ. Toxoplasmosis: A Pathway to Neuropsychiatric Disorders. Neurosci Biobehav Rev (2019) 96:72–92. doi: 10.1016/j.neubiorev.2018.11.012

  • CrossRef
  • Google Scholar

• 274

  FrickelEMHunterCA. Lessons From Toxoplasma: Host Responses That Mediate Parasite Control and the Microbial Effectors That Subvert Them. J Exp Med (2021) 218:11. doi: 10.1084/jem.20201314

  • CrossRef
  • Google Scholar

• 275

  RastogiSXueYQuakeSRBoothroydJC. Differential Impacts on Host Transcription by ROP and GRA Effectors From the Intracellular Parasite Toxoplasma gondii. mBio (2020) 11:3. doi: 10.1128/mBio.00182-20

  • CrossRef
  • Google Scholar

• 276

  AndradeWASouza MdoCRamos-MartinezENagpalKDutraMSMeloMBet al. Combined Action of Nucleic Acid-Sensing Toll-Like Receptors and TLR11/TLR12 Heterodimers Imparts Resistance to Toxoplasma gondii in Mice. Cell Host Microbe (2013) 13:142–53. doi: 10.1016/j.chom.2012.12.003

  • CrossRef
  • Google Scholar

• 277

  KoblanskyAAJankovicDOhHHienySSungnakWMathurRet al. Recognition of Profilin by Toll-Like Receptor 12 is Critical for Host Resistance to Toxoplasma gondii. Immunity (2013) 38:1119–30. doi: 10.1016/j.immuni.2012.09.016

  • CrossRef
  • Google Scholar

• 278

  YarovinskyF. Innate Immunity to Toxoplasma gondii Infection. Nat Rev Immunol (2014) 14:2109–21. doi: 10.1038/nri3598

  • CrossRef
  • Google Scholar

• 279

  FischDBandoHCloughBHornungVYamamotoMShenoyARet al. Human GBP1 is a Microbe-Specific Gatekeeper of Macrophage Apoptosis and Pyroptosis. EMBO J (2019) 38:13:e100926. doi: 10.15252/embj.2018100926

  • CrossRef
  • Google Scholar

• 280

  PandoriWJLimaTSMallyaSKaoTHGovLLodoenMB. Toxoplasma gondii Activates a Syk-CARD9-NF-kappaB Signaling Axis and Gasdermin D-Independent Release of IL-1beta During Infection of Primary Human Monocytes. PLoS Pathog (2019) 15:8:e1007923. doi: 10.1371/journal.ppat.1007923

  • CrossRef
  • Google Scholar

• 281

  KimBLeeYKimEKwakARyooSBaeSHet al. The Interleukin-1alpha Precursor is Biologically Active and is Likely a Key Alarmin in the IL-1 Family of Cytokines. Front Immunol (2013) 4:391. doi: 10.3389/fimmu.2013.00391

  • CrossRef
  • Google Scholar

• 282

  DowerSKKronheimSRHoppTPCantrellMDeeleyMGillisSet al. The Cell Surface Receptors for Interleukin-1 Alpha and Interleukin-1 Beta Are Identical. Nature (1986) 324:6094266–8. doi: 10.1038/324266a0

  • CrossRef
  • Google Scholar

• 283

  AlvarJVelezIDBernCHerreroMDesjeuxPCanoJet al. Leishmaniasis Worldwide and Global Estimates of Its Incidence. PLoS One (2012) 7:5:e35671. doi: 10.1371/journal.pone.0035671

  • CrossRef
  • Google Scholar

• 284

  ChappuisFSundarSHailuAGhalibHRijalSPeelingRWet al. Visceral Leishmaniasis: What Are the Needs for Diagnosis, Treatment and Control? Nat Rev Microbiol (2007) 5:11873–82. doi: 10.1038/nrmicro1748

  • CrossRef
  • Google Scholar

• 285

  LefevreLLugo-VillarinoGMeunierEValentinAOlagnierDAuthierHet al. The C-Type Lectin Receptors Dectin-1, MR, and SIGNR3 Contribute Both Positively and Negatively to the Macrophage Response to Leishmania infantum. Immunity (2013) 38:51038–49. doi: 10.1016/j.immuni.2013.04.010

  • CrossRef
  • Google Scholar

• 286

  Arango DuqueGJardimAGagnonEFukudaMDescoteauxA. The Host Cell Secretory Pathway Mediates the Export of Leishmania Virulence Factors Out of the Parasitophorous Vacuole. PLoS Pathog (2019) 15:7:e1007982. doi: 10.1371/journal.ppat.1007982

  • CrossRef
  • Google Scholar

• 287

  ShioMTChristianJGJungJYChangKPOlivierM. PKC/ROS-Mediated NLRP3 Inflammasome Activation is Attenuated by Leishmania Zinc-Metalloprotease During Infection. PLoS Negl Trop Dis (2015) 9:6:e0003868. doi: 10.1371/journal.pntd.0003868

  • CrossRef
  • Google Scholar

• 288

  Hergueta-RedondoMSarrioDMolina-CrespoAMegiasDMotaARojo-SebastianAet al. Gasdermin-B Promotes Invasion and Metastasis in Breast Cancer Cells. PLoS One (2014) 9:3:e90099. doi: 10.1371/journal.pone.0090099

  • CrossRef
  • Google Scholar

• 289

  XuBJiangMChuYWangWChenDLiXet al. Gasdermin D Plays a Key Role as a Pyroptosis Executor of non-Alcoholic Steatohepatitis in Humans and Mice. J Hepatol (2018) 68:4773–82. doi: 10.1016/j.jhep.2017.11.040

  • CrossRef
  • Google Scholar

• 290

  ForstnerG. Signal Transduction, Packaging and Secretion of Mucins. Annu Rev Physiol (1995) 57:585–605. doi: 10.1146/annurev.ph.57.030195.003101

  • CrossRef
  • Google Scholar

• 291

  ZhangJYuQJiangDYuKYuWChiZet al. Epithelial Gasdermin D Shapes the Host-Microbial Interface by Driving Mucus Layer Formation. Sci Immunol (2022) 7:68:eabk2092. doi: 10.1126/sciimmunol.abk2092

  • CrossRef
  • Google Scholar