NLRP3 inflammasome consists of three components including NLRP3 scaffold, a pyrin domain (PYD), and a caspase recruitment domain (CARD), known as ASC, and caspase-1 (8). NLRP3 belongs to NLR protein family which includes 22 members widely expressed in human histiocytes, such as dendritic cells, macrophages, and monocytes. NLRP3 contains three segments ( Figure 2 ): (a) PYD in amino-terminal; (b) a NACHT domain in central part: executes the function of NLRP3 self-association via ATPase activity; (c) a leucine-rich repeat domain (LRR domain) in carboxy-terminal: depresses NLRP3 activation by inhibiting the ATPase activity of the NACHT domain. ASC includes PYD in amino-terminal and CARD in carboxy-terminal, which interact with each other to activate caspase-1. Caspase-1 consists of three parts from amino-terminal to carboxy-terminal: CARD, central large catalytic domain (p20), and small catalytic subunit domain (p10) (9, 10).

All of the substructures execute specific function in NLRP3 inflammasome assembly. Activated by upstream signals, the NACHT domains of NLRP3 interact with each other to induce NLRP3 oligomerization. And then the homotypic PYD-PYD interaction promotes ASC recruitments and formation of nucleates helical ASC filament. ASC recruits and activates caspase-1 via homotypic CARD-CARD interactions. At last, the clustered caspase-1 cleaves to a complex of p33 which comprises CARD and p20, a formation with proteolytical activation (11, Figure 2 ). NIMA-related kinase 7 (NEK7) is a new component in recent studies ( Figure 2 ). Genetic research showed that NEK7 functioned as an indispensable component to NLRP3 inflammasome activation (12). NEK7 belongs to the family of mammalian NIMA-related kinases and is a serine or threonine kinase involved in mitosis. In the mediation of potassium efflux and mitochondrial reactive oxygen species (ROS), NEK7 binds to LRR domain of NLRP3, which is essential to NLRP3 inflammasome activation (13).

The activation of NLRP3 inflammasome includes two steps: firstly, it should be primed, sequentially activated. Priming is a preparation stage for subsequent responses. On the one hand, upregulated expression of NLRP3, caspase-1, and pro-IL-1β is induced by gene transcription and activation of nuclear factor-κB (NF-κB). This process is initiated through three ways ( Figure 2 ): (a) PRRs, such as NOD2 or TLRs, recognize PAMPs and DAMPs; (b) cytokines directly activate NF-κB pathway, including tumor necrosis factor (TNF) and IL-1β; (c) lipopolysaccharide (LPS) upregulates IL-1β transcription by shifting specific metabolism status (14–16). On the other hand, NLRP3 post-translational modifications (PTMs) are induced in the priming stage. NLRP3 is stabilized into a state in which the NLRP3 activity is auto-suppressed, but it still can respond to various signals (17). Importantly, NLRP3 PTMs occurs in the whole process of NLRP3 inflammasome activation, even in the unstimulated stage (18).

PAMPs and DAMPs stimuli varies in chemical properties and structures, and the direct binding of stimuli to NLRP3 are rarely detected. It is hypothesized that NLRP3 may sense common upstream signals which are induced by NLRP3 activators. This character of indirect activation is the core to understand molecular mechanism of NLRP3 activation. The comprehensive signal has not been determined, and relevant researches are contradictory. The common upstream signals identified include K⁺ efflux, Ca²⁺ flux, Cl⁻ efflux, mitochondrial dysfunction, ROS production, lysosomal damage, trans-Golgi disassembly, metabolic changes, and so on. There are three typical consensus models of common upstream signals.

By recognizing pathological infections and endogenous danger signals, NLRP3 inflammasome can trigger immune responses and inflammatory responses. The regulation of NLRP3 inflammasome activation is as critical for immune regulation in immune homeostasis, as for inflammose function itself. The aberrant regulation can induce NLRP3 inflammasome overactivation and excessive cytokine production, resulting in skewed inflammatory responses, which might induce adaptive immune dysfunction. The statue can be switched from physiological defense to pathogenic damage by aberrant regulation.

The strict regulation of NLRP3 inflammasome activation is essential to maintain immune system homeostasis. More importantly, accurate understanding of the regulatory mechanisms is crucial to identify triggers of autoimmune diseases involved in NLRP3 inflammasome, and treatments targeted on it may show great therapeutic potential. Various potential regulation mechanisms have been reported, such as cell surface associated mucin 1, MicroRNA (miRNA), small heterodimer partner ( Table 1 ). Clarifying traits of regulations from the following aspects might contribute to a more comprehensive understanding: positive or negative regulation; the specific stage on which the regulator targets, including priming stage and activation stage; and specific subcellular location, such as mitochondria and Golgi apparatus ( Table 1 ).

PTMs of NLRP3 can participate in various phases of NLRP3 inflammasome activation and regulate innate immunity. Covalent additions including ubiquitylation, phosphorylation, and sumoylation have been reported in NLRP3 PTMs. For example, sumoylation by the protein E3 SUMO protein ligase MUL1 (also known as MAPL) depresses NLRP3 activation. However, both promoted and suppressed effect of phosphorylation on NLRP3 have been detected (54, 55). In addition, PTMs can interact with each other. Phosphorylation can promote deubiquitylation by interaction between BRCA1/BRCA2-containing complex subunit 3 and LRR domain of NLRP3 (54). It indicates that regulation of NLRP3 activation is a delicate and complex process.

Overreaction of innate immune responses may cause overactivity of cytokines and pyroptosis, which contribute to inflammatory and autoimmune diseases, the same as overreaction of skewed adaptive immune responses may cause hypersensitivity. Therefore, identifying critical triggers of the unbalanced immunoregulation would be an important direction in the future researches.

Inflammatory bowel disease (IBD) is the most common intestinal tract disorders, characterized by dysfunction of innate immunity and aberrant inflammation in intestinal mucosa. It is comprised mainly of Crohn’s disease (CD) and ulcerative colitis (UC) (133). Though the specific pathogenesis of IBD has not been elucidated until now, several researches have revealed that NLRP3 inflammasome activation is upregulated in IBD. Serum concentration of NLRP3 is elevated, positively correlated with serum IL-1β level and severity of IBD patients (134). Furtherly, NLRP3 inflammasome is activated in early stage of CD patients, whereas in late stage of UC patients, which implies that there are differences between the development of UC and DC (135).

Downstream effects of NLRP3 inflammasome activation contribute to chronic inflammation, alterations in innate immune responses and disorders in mucosal immune response. These effects mainly include the consequent processes: pro-inflammatory cytokine release, macrophage hyperactivation with uncontrolled damage, and pyroptosis (136). In vitro, Monocarboxylate Transporter 4 contributed to intestinal enterocyte pyroptosis mediated by Caspase-1 through ERK1/2-NF-κB pathway, which can promote intestinal inflammation (58). Recent studies show that non-canonical endogenous irritants such as non-infectious stress conditions can also affect NLRP3 inflammasome activation. Fasting-mimicking diet reduced the expression of NLRP3 inflammasome and CD4⁺ T cells percentage in peripheral blood and spleen to alleviate intestinal inflammation, which indicated that calorie restriction might modulate immune response via NLRP3 inflammasome (61). Yun et al. presented that NLRP3 inflammasome was removed by ubiquitin-mediated degradation, which was promoted by autophagy under nutrient deprivation (62). The downstream proinflammatory cytokines IL-1and IL-17E/25 could be suppressed to strengthen intestinal barrier function (62). CircRNA HECTD1 (circHECTD1) can alleviate UC by inhibiting NLRP3 inflammasome. And in Caco-2 cells, circHECTD1 can induce human antigen R (HuR) via miR-182-5p, which contributes to NLRP3 inflammasome activation by autophagy (63). NLRP3 inflammasome may have a double effect on IBD: some reports showed that IL-1β and IL-18 play a protective role in gastrointestinal inflammation. Oxazolone can stimulate maturation of pro-caspase-1 and pro-IL-1β, and colitis induced by oxazolone can be ameliorated by exogenous IL-1β or IL-18 (59). Higher sensitivity to oxazolone treatment and decreased IL-1β or IL-18 production were detected in NLRP3^(−/−) mice compared to wild-type mice, which indicates that IL-1β and IL-18 derived from NLRP3 inflammasome can protect against inflammation in gastrointestinal mucosa (59). In addition, IL-1β contributes to enhanced host defense against Clostridium difficile and Citrobacter rodentium during acute affection (137, 138). It induces ASC-dependent CXCL1 production to recruit neutrophils to the intestine, protects epithelial integrity, and reduces colonization (137, 138). There are several explanations for the protective effect. Marianne et al. presented that protein tyrosine phosphatase non-receptor 22 mediates dephosphorylation of NLRP3 inflammasome, resulting in its activation and release of mature IL-1β in mouse models (60). Under a physiological condition, this process contributes to effective host defense against harmful pathogens leading to gastrointestinal disorder and subsequent reconstitution (60). Meanwhile, another study had shown that NLRP3 inflammasome could promote neutrophil chemotaxis and antimicrobial secretions of the colon to sustain intestinal homeostasis (57). When epithelial barrier was destroyed, microbiota recruited immune cells to the lamina propria, and NLRP3 inflammasome activated in these immune cells played destructive effect (57). Therefore, NLRP3 inflammasome may have different effects in specific conditions, including physiological condition, infection by invading pathogenic bacteria and involving in innate immune disorder.

NLRP3 inflammasome inhibitors have been demonstrated to be effective in experimental models of IBD. Most inhibitors have a commonly downregulated effect on NLRP3, caspase-1, and pro-inflammatory cytokines. So far, therapeutic targets of NF-κB, Nuclear factor E2-related factor-2 (Nrf2), and ROS have been widely studied. Naringin, an activating ligand of peroxisome proliferator-activated receptor γ (PPARγ), can significantly decrease disease activity indexes (DAI), pathological damage of colon, and inflammation severity (64). Naringin alleviated UC via pressing NLRP3 inflammasome by activating PPARγ and degrading subsequent NF-κB activation (64). In a murine TNBS-induced colitis model, carboxyamidotriazolez downregulated NF-κB pathway by reduction of NF-κB p65 expression and phosphorylation of IκBα (65). Phloretin and Growth differentiation factor 11 play an anti-inflammatory effect targeting on the same pathway (66, 67). Nrf2 is a negative regulator for NLRP3 inflammasome by inhibiting priming of NLRP3 inflammasome (68). Cardamonin is a natural herbal extract of Alpinia katsumadai Hayata. Nrf2 and its target genes NQO1, Trx1, SOD2 and HO-1, especially NQO1, was elevated by cardamonin, which has the effect to depress NLRP3 inflammasome activation in a mouse model (69). And upregulation of Nrf2 has been detected after treatment of Resveratrol and Hydrogen sulfide (H₂S) (70, 71). ROS is considered as a second messenger in pro-inflammatory responses. H₂S can also reduce ROS production to prevent inflammation (71). Moreover, therapeutic strategies focused on miRNA has attracted more attention, Cinnamaldehyde can decrease MicroRNA-21 and miR-155 levels in colons and macrophages to ameliorate DSS-induced colitis (72). Recent studies showed that new mode of administration can also promote the efficacy of NLRP3 inflammasome inhibitors. The combined administration of BBG (a P2X7R blocker) and OLT1177 (a selective NLRP3 inhibitor) effectively alleviates UC by complementary effects (73). The effect of NLRP3 inflammasome inhibitors in IBD has not been comprehensively understood, which deserves further study.

Psoriasis is a chronic inflammatory skin disease mediated by immune responses. In psoriasis biopsy, the expression of NLRP3, caspase-1, and IL-1β was significantly upregulated compared to non-lesional psoriatic skin (139). The single nucleotide polymorphisms (SNPs) studies show that the genetic mutations in NLRP3 are associated with psoriasis susceptibility in Chinese Han population (140). And the genetic mutations in CARD8-C10X (rs2043211) are associated with Psoriatic arthritis (PsA) in northern Swedish population (141). All these findings indicate that NLRP3 inflammasome may be involved in the occurrence and development of psoriasis.

PlxnB2 and its ligand (such as CD100) participate in neuronal development and immune responses (75). The bound of soluble CD100 to PlxnB2 can upregulate NF-κB pathway, which induces NLRP3 inflammasome activation in keratinocytes of psoriasis patients (75). In fibroblasts deriving from patients with psoriasis, abnormal inflammasome activity can be induced by downregulation of tristetraprolin TTP (76). TTP can directly target the degradation of NLRP3 mRNA; therefore, TTP downregulation may contribute to pathogenesis of psoriasis via NLRP3 inflammasome activation (76). Verma et al. found that TNF-α could activate NLRP3 inflammasome, which is independent of priming signals, and caspase-1 reactivity, plasma IL-1β and IL-18 are reduced in psoriasis patients treated with anti-TNF therapy (77). In mouse model of psoriasis, NLRP3 inflammasome keratinocytes can be activated by TNF-α to induce inflammation, which was induced by inhibiting autophagy via PI3K/AKT/mTOR signaling pathway (142). Overexpression of lncRNA MEG3 could alleviate inflammation by promoting autophagy (142). Serum amyloid A (SAA) serves as an important trigger to promote expression of IL-1β by activating NF-κB pathway in psoriatic keratinocytes (78). And IL-1β plays a key role in the skin diseases mediated by T helper type 17 cells (78). In vitro, miR-155 silencing can depress NLRP3/caspase-1 signal pathway to alleviate inflammatory responses (79). In summary, these findings indicate that CD100/PlxnB2, TTP, TNF, miR-155, and SAA might be potential therapeutic targets for psoriasis.

Herbal extracts have been demonstrated to be effective treatment for psoriasis. In psoriasis mouse models induced by imiquimod, the expression of TLR7, TLR8, p-NF-κB, and NLRP3 were obviously suppressed by administration of Datura metel L (80). The production of key inflammatory cytokines including IL-1β, IL-17, and IL-23 was also inhibited, which implied that Datura metel L. plays a protective role by depressing the pathway of TLR7/8-MyD88-NF-κb-NLRP3 (80). Paeonia lactiflora Pallas extract and BAY11-7082 have an inhibitory effect against immune responses in keratinocytes probably by the similar pathway (79, 81). In addition, cycloastragenol specifically inhibits macrophages infiltration in dermis and pyroptosis mediated by NLRP3 inflammasome in mouse models (81). IL-1 inhibition might be another promising therapeutic strategy. Wan et al. reported a dissolvable microneedle, which consists of Cas9 RNP nanocomplexes and dexamethasone nanoparticles (82). The microneedle can be internalized by keratinocytes and immune cells, and disrupted NLRP3 inflammasome selectively to alleviate skin inflammations in a mouse model of psoriasis (82). Of note, new-onset plaque psoriasis has been shown to be a side effect in the RA patients treated with anti-IL-1 therapy (74). The role of NLRP3 inflammasome in psoriasis pathogenic mechanism is complicated, and the researches are comparatively limited, which deserves further studies.

Rheumatoid arthritis (RA) is a common chronic autoimmune disease characterized by persistent synovial inflammation, pannus formation, destruction of cartilage and small diarthrodial joints, which is mainly caused by autoantibody secretion and aberrant immune responses (143). Various NLRP3-releated SNPs have been shown to be associated with susceptibility of RA. NLRP3 SNPs are associated with susceptibility of RA and anti-TNF responses in Caucasian population (144). In addition, genetic mutations of NLRP3 inflammasome may increase the risk of stroke and TIA in Swedish population, but not of myocardial infarction and angina pectoris (145).

Several studies have shown the hyperactivity of NLRP3 Inflammasome and downstream factors in RA. The intracellular levels of NLRP3, active caspase-1, pro-IL-1β, and active IL-1β in whole blood cells are increased in active RA patients (146). This increased level can also be detected with the treatment of TLR4 or TLR3 agonist (146). Guo et al. found that MCC950, a selective NLRP3 inhibitor, is able to depress NLRP3 inflammasome activation in monocyte and macrophages to infiltrate into the synovia, resulting in lesser joint inflammation and bone destruction (88). It indicates that NLRP3 Inflammasome is involved in the pathogenesis of RA. NLRP3 inflammasome activation has not been detected in fibroblast-like synoviocytes (FLS), which suggests that FLS may not produce IL-1β mediated by NLRP3 inflammation (147). TLR1-9 have been demonstrated to play a modulatory role in joint inflammation in the pathogenesis of RA (148). Downregulation of NOD2 gene expression can decrease NF-κB and pro-inflammatory cytokines in FLS of RA patients, which indicates that NOD2 may promote NLRP3 Inflammasome activation by effecting the priming stage (149). Both in FLS and human umbilical vein endothelial cells of RA patients, TNF-α/CRT dual signaling promotes NLRP3 Inflammasome activation via enhancing the effect of caspase-1 (85). TNF-α may serve as an initiator for HuR translocating to mediate NLRP3 Inflammasome activation (85). The typical activated models of Ca²⁺ and P2X7 are also detected to initiate activation of NLRP3 Inflammasome in RA patients (86).

Zhao et al. demonstrated that NLRP3 Inflammasome promotes Th17 cell differentiation to enhance the adaptive immune dysfunction of RA (150). Th17 has been proven to have a vital role in the downstream cascade reactions of NLRP3 inflammasome in RA. Jin et al. firstly found that protectin DX downregulates Th17 cells and pro-inflammatory cytokines and upregulates Tregs and anti-inflammatory cytokines by inhibiting NLRP3 inflammasome activation via miR-20a (89). Tofacitinib effectively ameliorates the severity of RA by restoring Treg/Th17 cell balance via reducing NLRP3 inflammasome activation in arthritic joints and draining lymph nodes (87). NLRP3 inflammasome can also mediate secretion of Fas-associated death domain, which is a pivotal adaptor molecule in innate immunity and inflammation (151). However, the expression of NLRP3 and pro-caspase-1 was decreased in the peripheral neutrophils (152). The active caspase-1 expression was increased, which was positively correlated with serum level of IL-18, which suggested that IL-18 mediated by active caspase-1 plays a pro-inflammatory role in neutrophils of RA, independently of NLRP3 inflammasome (152). Thus, different cell types should be noted in the pathogenesis of RA.

Taraxasterol exerts anti-inflammatory effects by depressing NLRP3 inflammasome pathway via downregulating the expression of NF-κB in RA patients (90). Celastrol, a quinone-methylated triterpenoid extracted from Tripterygium wilfordii, alleviates RA inflammation by suppressing the ROS/NF-κB/NLRP3 pathway (91). In collagen-induced arthritis mouse models, Punicalagin (an active substance extracted from pomegranate peel) inhibits phenotype polarization and pyroptosis of M1 macrophages by downregulating NF-κB signaling (92). Hsa_circ_0044235 has been found to inhibit NLRP3-mediated pyroptosis in FLSs (93). Other potential therapeutic strategies focus on negative regulation of NLRP3 inflammasome. Human umbilical cord blood-derived MSCs suppress the expression of NLRP3 Inflammasome via a paracrine loop of IL-1β signaling in CIA mouse models and mononuclear cells from RA patients (94). The deficiency of A20 in macrophages can enhance the effect of NLRP3 inflammasome by promoting the biological activity of caspase-1, IL-1β secretion, and pyroptosis in mouse models (44). Activation of NLRP3 Inflammasome and secretion of IL-1β can be inhibited by TTP expression and activation of TTP in both in vivo and in vitro models (95). TTP can be activated by dephosphorylation mediated by protein phosphatase 2A (PP2A), and Arctigenin (PP2A agonist) reduces monosodium urate (MSU) crystal-induced inflammation (95). It is indicated that TTP might be a potential target for inflammation induced by MSU crystals (95). These studies indicate that treatments aiming to inhibit NLRP3 inflammasome and IL-1β might be potential therapy for RA.

Systemic sclerosis (SSc) is an idiopathic autoimmune disease targeting on connective tissue, characterized by autoimmune dysfunction, microvascular vessel alterations, and skin fibrosis. The fibrosis is triggered by inflammatory response, in which innate immunity serves as a key factor. However, the precise pathogenesis hasn’t been clarified, and few effective treatments have been available until now.

In skin of patients with SSc, NLRP3 is upregulated and correlates positively with skin thickness (153). A resistant feature to skin fibrosis can be detected in NLRP3^(−/−) mice and ASC ^(−/−) mice, which implies that there is a correlativity between SNPs of NLRP3 and SSc (96). MiR-155 participates in innate immunity and adaptive immunity (154, 155). MiR-155 is involved in pulmonary fibrosis, hepatic fibrosis, as well as wound site fibrosis (156–158), and IL-1β can induce the expression of miR-155 (159). The expression of miR-155 was significantly increased in SSc lung fibroblasts, and fibrosis could be driven by inflammasome-dependent expression of miR-155 (97). Furthermore, there are positive feedbacks between NLRP3 inflammasome and miR-155, which explains sustaining fibrosis in SSc (97). MiR-155 might be a potential target for SSc, deserving future study.

Artlett et al. detected that caspase-1 inhibitor decreased secretion of IL-1β, IL-18, and collagens in dermal and lung fibroblasts of SSc, and reduced expression of α-smooth muscle actin in dermal fibroblasts (96). Shinohara presented that host receptors can identify pathogens to induce autoimmunity, which implies that infections and autoimmunity are closely connected (160). B19V infection induces caspase-1 mediated by NLRP3 inflammasome in monocytes of SSc patients (98). The expression of IL-1β and TNF-α can be induced by stimulus such as lipopolysaccharides (98). It indicates that viral components can enhance the sensitivity of NLRP3 inflammasome activation in monocytes (98). These findings may provide potential prevention strategy for SSc.

Type 1 diabetes (T1D) is an autoimmune disease targeting insulin-producing pancreatic β-cells specifically mediated by T lymphocyte (161). Both innate immunity and adaptive immunity participate in the development of T1D, and NLRP3 inflammasome acts as an important component of innate immunity to induce insulitis and β-cell death (162, 163). Polymorphisms of NLRP3 inflammasome-related gene correlate with T1D. Pontillo et al. found that SNPs in NLRP3 had a correlation specifically with T1D in Brazilian population (164). In Norwegian population and Chinese Han population, NLRP1 was associated strongly with T1DM (165). Wu et al. found that SNPs in NLRP3 correlated specifically with T1D, especially in Latin American population (166). In Slovenian population, the association of NLRP3 polymorphisms with T1D has not been observed (167). It is needed to confirm the specific gene polymorphisms of NLRP3 in different populations.

The important role of IL-1β in the pathogenesis of T1D has been determined in previous studies. IL-1β modulates pro-inflammatory cells to migrate into pancreatic islet, inducing direct cytotoxicity and β-cell apoptosis, which depends on the dose of IL-1β in T1D rat models (99, 100). Interestingly, NLRP3 inflammasome played a protective role in early stage of T1D in IRAK-M ^(−/−) NOD mice (168). In human islets, NLRP3 inflammasome can be activated, and secretion of IL-1β increases by the presence of LPS and ATP (102). As an upstream factor activating IL-1β, NLRP3 inflammasome may have a potential function in T1D. Resident peritoneal macrophages promote inflammation by inducing inflammatory cytokine/chemokine secretion such as IL-1β and upregulating the receptor expression of these proinflammatory cytokine/chemokine (103). Nitric oxide production is mediated by upregulated NLRP3/iNOS (nitric oxide synthase) pathway, which contributes to the proinflammatory state of resident PMs (103).

NLRP3 inflammasome has been shown to initiate and participate chronic complications of diabetes. Hyperglycemia can activate NLRP3 inflammasome, promote secretion of inflammatory cytokines, and trigger cascade of inflammatory response, finally inducing diabetic nephropathy, diabetic retinopathy, and so on (104, 169). Mitochondrial DNA activates NLRP3 inflammasome in endothelial cells via Ca²⁺ influx and mitochondrial ROS generation, which mediates endothelial dysfunction and vascular inflammation in diabetes complications (105). NLRP3 inflammasome activation can be detected in urothelial cells (170). It induces loss of in nerve density and Aδ-fibers, and leading to insensitivity of bladder fullness, which is a specific diabetic bladder dysfunction symptom (170). Verapamil, a calcium channel blocker, can diminish the release of IL-1β and TNF-α into the vitreous fluid and decrease retinal ganglion cell loss in diabetic retinopathy via inhibiting NLRP3 inflammasome mediated by TLR4 (106). Verapamil can also reduce pancreatic islets shrinkage and enhanced CD34 expression by interfering NLRP3 inflammasome assembly (106). In streptozotocin-induced mice with diabetic cardiomyopathy, the expression of NLRP3 inflammasome, IL-1β, and IL-18 in cardiac tissues was induced by nuclear NF-κB translocation, which can be inhibited by Scutellarin treatment (107). These researches imply that NLRP3 inhibitors could serve as a potential target for patients with diabetes.

MCC950, as an inhibitor of NLRP3 inflammasome, has been demonstrated to be a compelling treatment for diabetes in mouse models (171). Gao et al. found that Ginsenoside Rg1, a major active ingredient in ginseng, a traditional herb for diabetes in China, had a function to weaken NLRP3 activity in the liver and pancreas (108). In addition, low-methoxyl pectin can mediate decrease of NLRP3 inflammasome activation. And it can enhance cecal barrier function and shape intestinal homeostasis to ameliorate gut-pancreatic immune environment (109, 172). Low-methoxyl pectin may serve as a promising prevention drug of T1D. The TLR2/4, NF-κB, and NLRP3 inflammasome pathways are upregulated in intestinal tissues of NOD mice, which promotes the secretion of downstream signaling proteins such as IL-1β and IFN-γ (110). These downstream signaling proteins can induce activation and differentiation of T cells and the migration of these diabetogenic T cells to the pancreas (110). We propose that immunotherapy targeting on NLRP3 inflammasome is a promising approach to treat T1D.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by production of autoantibodies against nuclear components, deposition of immune complex, and multiorgan damage resulting from aberrations of immune response. Gene polymorphisms of NLRP3 were significantly associated with susceptibility of SLE in Latin American individuals (173). However, in Chinese Han population, association between NLRP3 SNPs and SLE susceptibility has not been observed (174). It is warranted to study the relationship of gene polymorphisms of NLRP3 with SLE susceptibility in different populations. The expression of NLRP3 inflammasome, AIM2, and caspase-1 was increased in renal tissues, especially there was a positive relationship between the expression level of NLRP3 inflammasome and the activity index score in patients with SLE (175). Furthermore, the expression of NLRP3 mRNA was upregulated in macrophages, and the expression of AIM2 mRNA was decreased in female SLE patients (176). Meanwhile, in male SLE patients, the expression of AIM2 mRNA was increased, and SNP of CARD8 resulted in susceptibility of patients (176). It implied that there is a gender-dependent difference in mechanism of inflammasome activation in SLE patients.

Both innate and adaptive immunity are involved in the pathogenesis of SLE. Double-strand DNA and immune complex could activate NLRP3 inflammasome in histiocytes to promote inflammatory response mediated by IL-1β and IL-18 (49). Nucleic acid components including microbial nucleic acids, endogenous DNA, and endogenous RNA-containing U1-small nuclear ribonucleoprotein (U1-snRNP) can activate NLRP3 inflammasome in human monocytes in vitro (114). Shin MS et al. discovered that immune complexes could activate NLRP3 inflammasome by upregulating NF-kB pathway in animal models and patients with SLE (111). The caspase-1 activation and IL-1β production of bone marrow-derived macrophages was decreased after it was transfected with Glycogen synthase kinase 3β (GSK-3β) siRNA (115). The administration of GSK-3β inhibitor could alleviate severe proteinuria and nephritis, and anti-dsDNA antibody production, deposition of immune complex, and circulating cytokines were depressed (115). Zhao et al. suggested that GSK-3 promotes renal inflammation by activating NLRP3 inflammasome and mediating IL-1β release (115). Caspase-1 was activated especially in CD14-positive and CD16-positive monocytes from SLE patients, which were positively correlated with serum titers of anti-double-stranded DNA antibodies and negatively correlated with serum levels of complement component 3 and platelet count (116). NLRP3 inflammasome could be activated by cyclic GMP-AMP synthase stimulator of interferon genes pathway to promote caspase-1 activation and IL-1β secretion (116). Neutrophil extracellular traps (NETs) were also found to participate in the pathogenesis of SLE. NETs are a network consisting of chromatin fibers and granule-derived antimicrobial peptides (177). The impaired clearance of NETs and increased release of NETs are promoted by low-density granulocytes (LDGs), which contribute to accumulation of NETs in human monocytes in vitro (112, 113). NETs can activate caspase-1 with releasing of proinflammatory cytokines IL-1β and IL-18, and promote the formation of immune complex and type I interferon (117). Interestingly, IL-18 in turn induces perpetual NETosis in human neutrophils, which results in a feed-forward inflammatory loop (117). A recent study found that milk fat globule-EGF factor 8 (MFG-E8) could reduce neutrophil migration, accumulation, phagocytosis, and NETosis via reducing surface CXCR2 expression in pristane-induced lupus and patients with SLE (118).

NLRP3 inflammasome plays an important role in the development of SLE. Podocytes are highly differentiated epithelial cells and a critical component of glomerular basement membrane (GBM), which play a core role in maintaining the function of glomerular filtration (178). In the later stage of SLE, the expression of NLRP3 inflammasome and caspase-1 could be detected in podocytes in murine lupus models (115). The production of ROS promotes NLRP3 inflammasome activation in the podocytes line (119). Importantly, TLRs (such as TLR4) is expressed in glomerular podocytes of normal mice, which implies that podocytes also possess immune function in physiological condition (179). In addition, IL-18 release mediated by NLRP3 inflammasome is a potential pathogenic factor in cutaneous lupus lesions. Type I IFN is reported to be a main risk factor of cardiovascular disease (180). The feed-forward inflammatory loop mentioned above can also be detected in endothelial progenitor cells (181). Xenon can reduce NF-κB/NLRP3 inflammasome activation to ameliorating renal function in mouse models with spontaneous LN (120). Honokiol and dibenzylideneacetone (Tris) dipalladium both have potential therapeutic effect against accelerated and severe type of lupus nephritis by suppressing NLRP3 inflammasome activation (121, 122). The former interferes NLRP3 inflammasome via reducing NF-κB activation, suppressing reactive oxygen production and mitochondrial damage, and inducing sirtuin 1/autophagy axis activation (121). And the latter can reduce p38 MAPK signaling pathways and regulate the autophagy/NLRP3 inflammasome axis (122). Cf-02 can treat acute onset of severe lupus nephritis in mice by inhibiting the NF-κB/NLRP3 inflammasome axis and regulating T cell functions differentially (123).

Interestingly, NLRP3 inflammasome might have immunosuppressive effect on SLE (182–184). The expression of TGF-β target genes was depressed by deficiency of NLRP3 and ASC in mice models of spontaneous lupus-like autoimmunity (182). NLRP3 and ASC are demonstrated to downregulate TGF-β receptor signaling through SMAD2/3 phosphorylation, which contributes to the immunosuppressive effect (182). There are more and more new drugs targeting the NLRP3 inflammasome in the treatment for SLE, and some show to be effective ( Table 2 ).

Autoimmune thyroid diseases (AITDs) are a series of thyroid diseases characterized by thyroid tissue damage and autoimmune disorders, including mainly Hashimoto’s thyroiditis (HT) and Graves’ disease (GD).

Guo et al. proposed firstly that multiple inflammasomes including NLRP3, NLRP1, NLRC4, and AIM2 participated in the development of AITDs (185). Excessive iodine promoted pyroptosis activity in thyroid follicular cells via the ROS-NF-κB-NLRP3 pathway which might be involved in the development of HT (186). However, Nagayama, Y., raised questions that Nthy-ori 3-1 cells aren’t capable of iodine uptake and the concentration of iodine (131). The role of NLRP3 inflammasome in Graves’ disease (GD) has not been reported so far.

It is reported that Yanghe decoction (a traditional Chinese herbal formulation) can alleviate autoimmune thyroiditis in rat models via downregulating NLRP3 inflammasome and adjusting the imbalance Th17/Treg (132). There are very few studies concerning the effect of NLRP3 inflammasome in the pathogenesis of AITDs, deserving further study.