Soudeh Ghafouri-Fard1
Hamed Shoorei2,3
Yadollah Poornajaf4
Bashdar Mahmud Hussen5,6
Yasaman Hajiesmaeili7
Atefe Abak8
Mohammad Taheri9,10*Ahmad Eghbali11*- 1Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- 2Clinical Research Development Unit of Tabriz Valiasr Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
- 3Department of Anatomical Sciences, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
- 4Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
- 5Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil, Iraq
- 6Center of Research and Strategic Studies, Lebanese French University, Erbil, Iraq
- 7Faculty of Health, York University, Toronto, ON, Canada
- 8Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- 9Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- 10Institute of Human Genetics, Jena University Hospital, Jena, Germany
- 11Anesthesiology Research Center, Mofid Children Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
NLR family pyrin domain containing 3 (NLRP3) is expressed in immune cells, especially in dendritic cells and macrophages and acts as a constituent of the inflammasome. This protein acts as a pattern recognition receptor identifying pathogen-associated molecular patterns. In addition to recognition of pathogen-associated molecular patterns, it recognizes damage-associated molecular patterns. Triggering of NLRP3 inflammasome by molecules ATP released from injured cells results in the activation of the inflammatory cytokines IL-1β and IL-18. Abnormal activation of NLRP3 inflammasome has been demonstrated to stimulate inflammatory or metabolic diseases. Thus, NLRP3 is regarded as a proper target for decreasing activity of NLRP3 inflammasome. Recent studies have also shown abnormal activity of NLRP3 in ischemia/reperfusion (I/R) injuries. In the current review, we have focused on the role of this protein in I/R injuries in the gastrointestinal, neurovascular and cardiovascular systems.
Introduction
NLR family pyrin domain containing 3 (NLRP3) gene is located on chromosome 1q44. The protein encoded by this gene is expressed in immune cells, especially in dendritic cells and macrophages and acts as a constituent of the inflammasome (1). In addition, NLRP3 is expressed in smooth muscle cells, endothelial cells, beta cells and cardiomyocytes (2–4). The pyrin-like protein encoded by this gene has a pyrin domain, a nucleotide-binding site (NBS) domain, and a leucine-rich repeat (LRR) motif. NLRP3 interacts with pyrin domain of apoptosis-associated speck-like protein comprising a CARD. Mutations in this gene have been detected in some organ specific autoimmune disorders. Being an element of the innate immune system, NLRP3 acts as a pattern recognition receptor (PRR) that identifies pathogen-associated molecular patterns (5). PRRs are receptors involved in the recognition of endogenous or exogenous invaders. These receptors can trigger an appropriate immune response to preserve the host integrity. Five groups of PRRs have been identified: Toll-like receptors, nucleotide oligomerization domain-like receptors, retinoic acid-inducible gene-I-like receptors, C-type lectin receptors, and absent in melanoma-2-like receptors (ALRs) (6). Among them, NLRP3 belongs to the NOD-like receptors. NLRP3 in addition to the adaptor ASC protein creates the caspase-1 activating complex NLRP3 inflammasome. In addition to recognition of pathogen-associated molecular patterns (PAMPs), it recognizes Damage-Associated Molecular Patterns (DAMPs).
NLRP3 and some other types of NLRs can create huge cytosolic protein complexes (probably hexamers or heptamers) called inflammasomes, which contribute to the initiation of cleavage and activation of procaspase-1 leading to proteolytic activation of pro- IL-1β and pro-IL-18 (7).
Activation of NLRP3 inflammasome needs a priming step that leads to up-regulation of NLRP3 and IL-1β in addition to NLRP3 post-translational licencing. A succeeding activation step results in the assemblage of the complex and caspase-1-mediated cleavage of pro-IL-18 and pro-IL-1β, permitting their release. The activation step can be triggered by a wide array of factors such as PAMPs and DAMPs, e.g. nigericin toxin, extracellular ATP, silica and cholesterol crystals (8).
In cooperation with the adaptor ASC protein, NLRP3 establishes the caspase-1 activating complex NLRP3 inflammasome. In its inactivate form, cytoplasmic NLRP3 is kept in a complex with HSP90 and SGT1. Crystalline uric acid and extracellular ATP released by injured cells result in the release of HSP90 and SGT1 from the NLRP3 inflammasome and recruitment of ASC protein and caspase-1 to this complex leading to activation of the pro-inflammatory cytokine, IL-1β (5). Consistent with this function, mutations in the NLRP3 gene have been found to be associated with elevation of IL-1β concentrations in the serum (9, 10). Moreover, incorrect induction of NLRP3 inflammasome has been reported to stimulate inflammatory or metabolic diseases. Thus, NLRP3 is regarded as a suitable target for decreasing activity of NLRP3 inflammasome. Recent studies have also shown abnormal activity of NLRP3 in ischemia/reperfusion (I/R) injuries. I/R injury is the tissue damage resulting from tissue reperfusion with blood after a period of ischemia (11). The lack of blood-born oxygen and nutrients in the course of ischemic period produces a condition in which the reestablishment of circulation leads to inflammation and oxidative damage via stimulation of oxidative stress instead of normal function (11). In the current review, we have focused on the role of this protein in I/R injuries in the gastrointestinal, neurovascular and cardiovascular systems.
Gastrointestinal I/R injury
The role of NLRP3 has been assessed in I/R injury in the liver and intestine (Figure 1). NLRP3 inflammasome activation in Kupffer cells can lead to I/R injury in liver cells. The NLRP3-associated hyper-inflammation can be prevented by mitophagy, a process that preserves mitochondrial homeostasis via removal of injured mitochondria. An in vivo study has shown significant inflammatory responses, over-activation of NLRP3 inflammasome and enhancement of PTEN-induced putative kinase1 (PINK1)-facilitated mitophagy in the process of hepatic I/R. Up-regulation of PINK1 has decreased I/R injury, production of reactive oxygen species (ROS), NLRP3 activation and inflammatory responses in the liver in animal models. In vitro anoxia/reoxygenation challenges could trigger NLRP3 activation in Kupffer cells and promote mitophagy. PINK1-mediated enhancement of mitophagy could inhibit NLRP3 activation and reverse the Kupffer cells-mediated inflammatory responses against hepatocytes (14). Another study has found hyper-activation of NLRP3 in both hepatocytes and macrophages of aged animals following I/R. NLRP3 silencing in macrophages has suppressed inflammatory responses and hepatic tissue injury in both young and aged animals. Notably, aged macrophages have exhibited hyper-activation of the STING/TANK- TBK1 signals following I/R. Inhibition of STING could block hyperactivity of NLRP3 signals and abnormal production of inflammatory cytokines in the mtDNA-induced bone marrow-derived macrophages of aged animals. Taken together, STING/NLRP3 axis has been shown to exert critical roles in the induction of inflammatory responses in aged macrophages (15).
Figure 1 A schematic illustration of the role of NLRP3 Inflammasome involved in the hepatic I/R injury. Mounting evidence has detected that STING/TBK1/NLRP3 signaling cascade can play a remarkable role in modulating innate immune activation and promoting liver IR injury in aged mice. STING can regulate the activation of NLRP3 signaling and excessive secretion of proinflammatory cytokines in the mtDNA-stimulated bone marrow-derived macrophages from aged mice. Moreover, STING upregulation in macrophages can elevate the detrimental role of aging in aggravating liver IR injury and intrahepatic inflammation (12). Furthermore, another research has illustrated that XBP1 can regulate macrophage cGAS/STING/NLRP3 activation via elevating macrophage self-mtDNA cytosolic leakage in liver fibrosis. Therefore, macrophage self-mtDNA can play an effective role as an intrinsic trigger for macrophage cGAS/STING activation that can be modulated through regulating XBP1/mitophagy (13).
Expression of the specific macrophage subunit of vacuolar ATPase (ATP6V0D2) has been reported to be up-regulated in hepatic macrophages after liver I/R surgery. Notably, ATP6V0D2 silencing has led to enhancement of secretion of inflammatory factors and chemokines, and subsequent activation of NLRP3 and exacerbation of hepatic damage. Mechanistically, the intensified activation of NLRP3 has been accompanied by the ATP6V0D2-regulated autophagic flux. ATP6V0D2 silencing has reduced establishment of autophagolysosome and exacerbated hepatic I/R injury via nonspecific V-ATPase activation (16).
Another study has shown that SET8 lessens I/R injury in liver via suppression of MARK4/NLRP3 inflammasome route (17). Hepatic I/R stimuli have been shown to increase expression of NLRP3 but not ASC. Lower I/R liver injury has been detected in NLRP3(-/-) mice, but not in ASC(-/-) and caspase-1(-/-) mice. NLRP3 knock-out mice has also exhibited decreased inflammatory response, neutrophils infiltration, ROS production, and apoptosis in the liver after I/R. Further functional studies have revealed that NLRP3 regulates chemokine-mediated function and neutrophil recruitment in an independent manner from its function in inflammasomes (18).
NLRP3 inflammasome has also been found to participate in the intestinal I/R injury. Down-regulation of NLRP3, ASC, caspase-1/11, or IL-1β has increased cell survival following intestinal I/R injury. Additionally, intestinal I/R injury has resulted in acute lung injury. The pathological features such as inflammation, ROS production and increased vascular permeability have been ameliorated by NLRP3 down-regulation. Additional studies have shown the critical role of NLRP3 expression in non-bone marrow-derived cells in the evolution of intestinal I/R-induced acute lung injury. In addition, activation of NLRP3 inflammasome in endothelial cells of lung has been shown to contribute to the intestinal I/R-induced acute lung injury (19).
I/R injury has also been found to disrupt barrier and induce cell death and pyroptosis. Notably, metformin has been found to protect intestinal barrier against I/R injury, reduce oxidative stress and the inflammatory responses, and decrease expression of NLRP3, cleaved caspase-1, and the N-terminus of GSDMD. In fact, the protective effect of metformin is exerted through modulation of TXNIP/NLRP3/GSDMD proteins (20) (Figure 2). Moreover, the autophagy inducing agent Rapamycin has been shown to attenuate intestinal I/R induced NLRP3 inflammasome activity, thus ameliorating inflammatory responses during the course of intestinal I/R injury (21). Table 1 summarizes the role of NLRP3 in I/R Injury in liver and intestine.
Figure 2 A schematic diagram of the role of NLRP3 involved in I/R Injury in intestine. Mounting evidence has demonstrated that inappropriate activation of NLRP3 could play an effective role in the progression of I/R injury in the intestine by creating an intracellular multi-protein complex known as NLRP3 inflammasome. As an illustration, a recent study has detected that Metformin could protect against intestinal I/R injury and decrease oxidative stress and the inflammatory response via downregulating pyroptosis-related proteins, containing NLRP3, active caspase-1, N-GSDMD, and the expression of TXNIP as well as the interaction between TXNIP and NLRP3 (20). Moreover, another research has figured out that Rapamycin through inducing the process of autophagy could attenuate intestinal I/R induced NLRP3 inflammasome activation (21).
Table 1 Role of NLRP3 in Gastrointestinal I/R Injury.
Neurovascular I/R injury
The role of NLRP3 has also been investigated in neurovascular I/R injury. An experiment in animal models of cerebral I/R induced by transient occlusion of middle cerebral artery and subsequent reperfusion surgery has shown down-regulation of SPATA2 expression in these models. SPATA2 has been shown to be co-localized with CYLD in neurons. Down-regulation of Spata2 has led to increased microglia, up-regulation of Tnfa, Il-1β, and Il-18, and elevation of the infarct size. Moreover, Spata2 knockdown has enhanced activity of P38MAPK, NLRP3 inflammasome and NF-κB signals (26). Another study has shown prompt activation of NLRP3 inflammasome in microglia following cerebral I/R injury onset and subsequent expression of this protein in neurons and microvascular endothelial cells afterwards. Besides, mitochondrial dysfunction has been reported to participate in activation of NLRP3 inflammasome in microglia. Thus, mitochondrial protectors could block NLRP3 inflammasome activity in art models of cerebral I/R. Taken together, NLRP3 inflammasome is activated in a cell type-dependent manner at different phases of cerebral I/R injury (27). Meanwhile, Nrf2 could inhibit activation of NLRP3 inflammasomes via regulating Trx1/TXNIP complex in cerebral I/R injury (28).
NLRP3 could also affect pathologic processes in acute cerebral infarction. In fact, ecosapentaenoic acid exerts its protective effects against acute cerebral infarction-associated inflammatory responses via suppression of activation of NLRP3 inflammasome (29). Another study has shown the impact of IMM-H004 on focal cerebral ischemia is exerted through modulation of CKLF1/CCR4- mediated NLRP3 inflammasome activation (30). Moreover, injection of IVIg could suppress NLRP1 and NLRP3 inflammasome-mediated death of neurons in cerebral I/R (31). Another study has shown down-regulation of low-density lipoprotein receptor (LDLR) expression following cerebral I/R injury. Notably, knockout of this gene in animal models has led to enhancement of caspase-1-dependent cleavage of GSDMD leading to severe pyroptosis of neurons. Mechanistically, defects in LDLR participate in the disproportionate NLRP3-facilitated maturation and release of IL-1β and IL-18 during ischemia which aggravates neurological defect and long-term cognitive function. Obstruction of NLRP3 has stunted pyroptosis of neurons in Ldlr-/- mice and cultured Ldlr-/- neurons following experimental stroke. Taken together, LDLR can modulate NLRP3-mediated pyroptosis of neurons and inflammatory responses in these cells after ischemic stroke (32). Similarly, defects in Uncoupling Protein 2 have been shown to enhances activity of NLRP3 inflammasome after hyperglycemia-associated exacerbation of cerebral I/R damage (33). Both chemical and siRNA-mediated inhibition of GSK-3β could improve neurological scores, decrease size of cerebral infarct, and reduce levels of NLRP3 inflammasome, cleaved-caspase-1, IL-1β, and IL-18. In fact, inhibition of GSK-3β activation could enhance autophagic activity (34). Table 2 shows the role of NLRP3 in neurovascular I/R Injuries.
Table 2 Role of NLRP3 in Neurovascular I/R Injury.
Myocardial I/R injury
NLRP3 inflammasome-associated pyroptosis is also involved in myocardial I/R injury. IP3R1 protein that regulates release of Ca2+ from endoplasmic reticulum has been shown to regulate pyroptosis through the NLRP3/Caspase-1 axis in myocardial I/R injury (67). Cardiac I/R injury can be alleviated through Calpain silencing which affects activity of the LRP3/ASC/Caspase-1 axis (68). Similarly, Formononetin has been shown to suppress the ROS-TXNIP-NLRP3 axis to ameliorate myocardial I/R injury in rats (69). In contrast, uric acid could aggravate myocardial I/R injury via ROS/NLRP3 pyroptosis pathway (70) (Figure 3).
Figure 3 A schematic illustration of the role of NLRP3 Inflammasome and its central role in the myocardial I/R injury. Accumulating evidence has illustrated that Luteolin could have a key role in protecting against myocardial I/R injury as opposed to Uric acid that could aggravate this injury through ROS/NLRP3 pyroptosis pathway. It has been reported that Luteolin could protect against myocardial I/R injury through TLR4/NF-kB/NLRP3 inflammasome cascade by downregulating the expressions of NLRP3, ASC, caspase-1, TLR4, MyD88 and the phosphorylations of IKKα, IKKβ, IκBα, and NF-κB (71).
Another study has demonstrated that diabetes aggravates myocardial I/R injury via influencing NLRP3 inflammasome-associated pyroptosis. Notably, suppression of inflammasome activation using BAY11-7082 has reduced the myocardial I/R injury in exposed animals. Consistently, both BAY11-7082 and the antioxidant N-acetylcysteine could reduce high glucose and hypoxia/reoxygenation-induced injuries in cardiomyocytes in vitro. Taken together, high glucose-induced NLRP3 inflammasome activation might depend on ROS production, and NLRP3 inflammasome-associated pyroptosis exacerbates myocardial I/R injury in diabetic animals (72). Table 3 shows the impact of NLRP3 in myocardial I/R Injury.
Table 3 Impact of NLRP3 in Myocardial I/R Injury.
Other types of I/R injury
The role of NLRP3 has also been assessed in limb, renal and testicular I/R injuries (Table 4). For instance, an experiment in rats has shown that hydrogen-rich saline decreases acute limb I/R-induced lung injury through decreasing levels of chemerin and NLRP3 (86).
Table 4 Role of NLRP3 in other types of I/R Injury.
Moreover, TLR4-associated increase in the activity of the platelet NLRP3 inflammasome has been reported to promote aggregation of platelets in a mice model of hindlimb ischemia (87). Similarly, I/R induced-acute kidney injury has been shown to be associated with over-expression of NLRP3 is overexpressed in chronic kidney disease (88). NLRP3 inflammasome is also implicated in the tissue injury and impairment of spermatogenesis caused by testicular I/R (89). Specific inhibitors of NLRP3 inflammasome, namely BAY 11-7082 (90) and Brilliant Blue G (BBG) (91) have been found to suppress effects of NLRP3 in an animal model of testicular I/R (89). Both agents could significantly reduce expressions of IL-1β and IL-18, diminish caspase-1 and caspase-3 levels and preserve spermatogenesis, representing a selective decrease in the activity of NLRP3 inflammasome (89). Moreover, NLRP3 knock-out mice has responded to I/R injury with a diminished level of induction of inflammatory and apoptosis cascade compared with wildtype animals. Thus, NLRP3 might be an appropriate target for new drugs for treatment of I/R injury after testicular torsion (92).
Discussion
NLRP3 is an essential element in the inflammasome whose activation by tissue injuries or pathogens leads to cleavage of caspase-1 by an autocatalytic process and release of inflammatory factors IL-1β and IL-18 (10). Thus, abnormal function of NLRP3 has been associated with development of several immune-related disorders. Consistently, NLRP3 targeting has been suggested as an interesting method for design of therapeutic modalities for management of NLRP3 inflammasome-related disorders (93). Several in vitro and animal studies have assessed the role of NLRP3 in gastrointestinal, neurovascular and cardiac I/R injuries. The results of these studies indicate critical role of this protein in induction of I/R injuries in different tissues. Since I/R injuries are associated with morbidity and mortality, targeting NLRP3 is a possible strategy for reduction of disease burden. In fact, inhibition of NLRP3 inflammasome activity can ameliorate inflammatory responses in intestinal or hepatic I/R injury. NLRP3 inflammasome can also aggravate pathologic events in ischemic brain injury, spinal cord injury and retinal injury. Thus, modulation of this cellular mechanism can be an effective strategy for treatment of a wide variety of disorders, particularly those associated with aging.
A number of known protective agents against cerebral injuries such as salvianolic acids, meisoindigo, acacetin, tetrandrine, bakuchiol, tomentosin and qingkailing have been shown to exert their effects through modulation of expression of NLRP3. Similarly, a number of substances such as formononetin, metformin, ethyl pyruvate, scutellarin, luteolin, OLT1177 (Dapansutrile), puerarin and biochanin have been found to protect against myocardial I/R injury via suppression of NLRP3. Thus, targeting NLRP3 is a promising strategy for management of different types of I/R injury.
Previous studies have reported association between NLRP3 genetic variants and risk of inflammatory conditions such as rheumatoid arthritis (94) and inflammatory bowel diseases (95). However, the exact impacts of these variants on I/R injuries have not been identified yet. Identification of the role of these variants in induction of I/R injuries would facilitate recognition of individuals being at risk of myocardial/cerebral injuries.
Future studies are needed to find novel substances for amelioration of NLRP3-mediated I/R injuries. Moreover, the functional interactions between NLRP3 and other molecules that contribute in the I/R injuries should be identified to further design more effective therapies for this kind of tissue injuries.
Author contributions
SG-F wrote the draft and revised it. MT designed and supervised the study. HSH, YP, BMH, YH, AA, and AE collected the data and designed the figures and tables. All authors contributed to the article and approved the submitted version.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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.
Abbreviations
tMCAO, transient middle cerebral artery occlusion; MCA, middle cerebral artery; CIS, Cerebral ischemic stroke; CSF1R, colony-stimulating factor 1 receptor; KCs, Kupffer cells; RGCs, retinal ganglion cells; LVECs, lung vascular endothelial cells; BMDMs, Bone marrow-derived macrophages; NRCMs, neonatal rat cardiomyocytes; NRVMs, Neonatal rat ventricle myocytes; CFs, cardiac fibroblasts; PRSCA, Primary rat spinal cord astrocytes; CMPK2, Cytidine monophosphate kinase 2; AIM2, absent in melanoma 2; MDA, Malondialdehyde; MPO, myeloperoxidase; TAC, total antioxidant capacity; AMH, anti-Müllerian hormone; TER, transepithelial electrical resistance; I-FABP), intestinal fatty binding protein; CAT, Catalase; Sirt-1, Sirtuin-1; H/R, Hypoxia/reoxygenation; OGD, oxygen and glucose deprivation; IP3R1, Intracellular ion channel inositol 1,4,5-triphosphate receptor; LDLR, Low-density lipoprotein receptor; BMVECs, brain microvascular endothelial cells; PMNs, polymorphonuclear leukocytes; HSPA8, heat shock protein family A; CHOP, C/EBP homologous protein; CCR4, chemokine receptor type 4; MARK4, microtubule affinity-regulating kinase 4; Drp1, dynamin-related protein 1; UCP2, uncoupling protein 2; CKLF1, Chemokine-like factor 1; PMC, Primary microglial cell; Trx1, hioredoxin1; Nrf2, Nuclear factor erythroid 2-related factor 2; TXNIP, thioredoxin interacting protein; AIM2, absent in melanoma 2; NLRC4, CARD domain containing 4; TLR, Toll-like receptor 2; TRAF6, TNF receptor-associated factor 6; PCN, Primary cortical neuron; XIAP, X-linked inhibitor of apoptosis protein; AMPK, AMP-activated protein kinase; CRAMP, antimicrobial peptide Cathelicidin.
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Keywords: NLRP3, ischemia/reperfusion, expression, biomarker, diagnosis
Citation: Ghafouri-Fard S, Shoorei H, Poornajaf Y, Hussen BM, Hajiesmaeili Y, Abak A, Taheri M and Eghbali A (2022) NLRP3: Role in ischemia/reperfusion injuries. Front. Immunol. 13:926895. doi: 10.3389/fimmu.2022.926895
Received: 23 April 2022; Accepted: 01 September 2022;
Published: 27 September 2022.
Edited by:
Benoit Pourcet, Université de Lille, FranceCopyright © 2022 Ghafouri-Fard, Shoorei, Poornajaf, Hussen, Hajiesmaeili, Abak, Taheri and Eghbali. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Mohammad Taheri, mohammad.taheri@uni-jena.de; Ahmad Eghbali, aegbali@yahoo.com