Next Article in Journal
Biochemical Composition and Biological Activities of Date Palm (Phoenix dactylifera L.) Seeds: A Review
Previous Article in Journal
Androgen Signaling in Uterine Diseases: New Insights and New Targets
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Biomolecules
Volume 12
Issue 11
10.3390/biom12111625
biomolecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Pyroptosis: A Newly Discovered Therapeutic Target for Ischemia-Reperfusion Injury

by
Yu Zheng
1,2,3,4,†,
Xinda Xu
1,2,3,4,†,
Fanglu Chi
1,2,3,4 and
Ning Cong
1,2,3,4,*
1
Department of Otorhinolaryngology, Eye Ear Nose and Throat Hospital, Fudan University, Shanghai 200031, China
2
Shanghai Clinical Medical Center of Hearing Medicine, Shanghai 200031, China
3
NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai 200031, China
4
Research Institute of Otorhinolaryngology, Fudan University, Shanghai 200031, China
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Biomolecules 2022, 12(11), 1625; https://doi.org/10.3390/biom12111625
Submission received: 1 October 2022 / Revised: 29 October 2022 / Accepted: 30 October 2022 / Published: 3 November 2022
Browse Figures
Review Reports Versions Notes

Abstract

:
Ischemia-reperfusion (I/R) injury, uncommon among patients suffering from myocardial infarction, stroke, or acute kidney injury, can result in cell death and organ dysfunction. Previous studies have shown that different types of cell death, including apoptosis, necrosis, and autophagy, can occur during I/R injury. Pyroptosis, which is characterized by cell membrane pore formation, pro-inflammatory cytokine release, and cell burst, and which differentiates itself from apoptosis and necroptosis, has been found to be closely related to I/R injury. Therefore, targeting the signaling pathways and key regulators of pyroptosis may be favorable for the treatment of I/R injury, which is far from adequate at present. This review summarizes the current status of pyroptosis and its connection to I/R in different organs, as well as potential treatment strategies targeting it to combat I/R injury.

1. Introduction

Ischemia-reperfusion (I/R) injury is caused by the resumption of blood supply (reperfusion) to an organ or tissue after a period of restricted blood supply, resulting in pathological processes that can lead to cell death and organ dysfunction. I/R injury can occur in many vital organs, including the brain, heart, and kidneys; it can also occur in less noticed organs, such as the cochlea and vestibule in the ear. The mechanisms of I/R injury comprise oxidative stress, sterile inflammation, calcium overload, mitochondrial dysfunction, and activation of various cell death pathways—including, but not limited to, apoptosis, necrosis, and autophagy [1]. Pyroptosis is another type of regulated cell death, characterized by cell membrane pore formation, pro-inflammatory cytokine release, and cell lysis [2]. It has previously been found that pyroptosis is closely related to the development of tumors [3]. Furthermore, recent studies have shown that pyroptosis also plays an important role in I/R injury. Because the current treatment and management of I/R injury are far from satisfactory [4], advances in understanding of the mechanisms of pyroptosis and its role in I/R injury may lead to innovative therapeutic strategies for treating patients with I/R-associated tissue inflammation and organ dysfunction. Therefore, in this review, we summarize the mechanisms of pyroptosis and its role as a potential therapeutic target for I/R injury.

2. Overview of Pyroptosis

Pyroptosis was first discovered by Zychlinsky et al. in 1992. They reported that the death of Shigella flexneri-infected macrophages was dependent on caspase-1 rather than caspase-3, which was then thought to be only involved in apoptosis [5]. In 1996, Chen et al. found that the invasion plasmid antigen B of Shigella flexneri could bind to the ICE (interleukin-1β-converting enzyme, caspase-1) directly, leading to the activation of enzymes in the infected macrophages and ultimately resulting in the death of those infected macrophages [6]. In 1999, Hersh et al. discovered that caspase-1 plays an indispensable role in this specific cell death mode, as caspase-1-knockout macrophages could not be induced into death by Shigella flexneri infection [7]. In 2001, this form of regulated cell death was named “pyroptosis” by Cookson and Brennan after they found a similar phenomenon in macrophages infected with Salmonella typhimurium [8]. Seven years later, fragmented DNA and a damaged cell membrane were found by Cookson et al. during the process of pyroptosis, which led to the release of intracellular content and triggered a severe inflammatory response [9]. In 2011, Kayagaki et al. found that caspase-11 was able to induce mouse macrophage death, which is essentially similar to caspase-1-mediated pyroptosis. They termed this caspase-11-mediataed pyroptosis as the “non-canonical pathway of pyroptosis” [10].
In 2015, Shao et al. conducted CRISPR-Cas9 nuclease screening for the whole genome of caspase-11- and caspase-1-mediated pyroptosis of mouse bone marrow macrophages, and they eventually identified gasdermin D (GSDMD) as the inflammatory caspase substrate through which caspases activated pyroptosis [11]. This study further proved that caspase-1 and caspase-4/5/11 specifically cleaved the linker between the amino-terminal gasdermin-N and the carboxy-terminal gasdermin-C domains in GSDMD, ultimately leading to cell pyroptosis, which was triggered only by the gasdermin-N domain.
GSDMD is a member of the human gasdermin superfamily, which consists of gasdermin A/B/C/D (GSDMA/B/C/D), gasdermin E (GSDME, also known as DFNA5), and DFNB59 (PJVK); the mouse gasdermin superfamily is composed of GSDMA1-3, GSDMC1-4, GSDMD, GSDME, and PJVK [12,13,14,15]. Among these proteins, GSDMD and GSDME are currently the most comprehensively researched in terms of pyroptotic death. Moreover, other than PJVK, these conserved proteins consist of two conserved domains, the N-terminal pore-forming domain (PFD) and the C-terminal repressor domain (RD) [16,17,18]. Most of the gasdermins’ N-terminals can trigger pyroptotic death, but this has not been found in PJVK so far [19,20]. In general, gasdermins maintain oligomerization through the interaction of two domains. When cells are stimulated by various factors, gasdermins are cleaved by certain caspases into the N-terminal PFD and the C-terminal RD. After dissociation, the PFD oligomerizes on the cell membrane to form pores and cause cell pyroptosis [21,22].

3. Mechanisms of Pyroptosis

It was formerly believed that there are two pathways of pyroptosis: one is the canonical pathway dependent on caspase-1, and the other is the non-canonical pathway dependent on human caspase-4/5 or mouse caspase-11. However, due to in-depth study in recent years, other pathways of pyroptosis have been found (Figure 1). The detailed mechanisms of pyroptosis and its pathways are discussed below.

3.1. Canonical Pathway

The canonical pathway of pyroptosis begins with cytoplasmic pattern recognition receptors (PRRs, also known as inflammasome receptors) recognizing pathogen-associated molecular patterns (PAMPs, e.g., glycans, lipopolysaccharides (LPSs)) or danger-associated molecular patterns (DAMPs, e.g., fibrinogen, heat shock proteins, reactive oxygen species (ROS)) [23,24]. With the stimuli of signal molecules such as bacteria or ROS, PRRs assemble with pro-caspase-1 and ASC to form inflammasomes [25,26,27]. Although a variety of PRRs, like NOD-like receptors (NLRs) and Toll-like receptors (TLRs), are involved in this process, only a subset of PRRs—including NLR family pyrin domain-containing (NLRP)1, NLRP3, and NLRP4; absent in melanoma 2 (AIM2); and pyrin—is known to be able to directly assemble inflammasomes [28]. Most inflammasomes are composed of the following: (i) leucine-rich repeat-containing proteins (NOD-like receptors, NLRs); (ii) pro-caspase-1; and (iii) the adapter apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD) (ASC) [29,30,31,32]. More specifically, ASC contains a pyrin domain (PYD) and a caspase activation and recruitment domain (CARD) [28]. CARD is indispensable in recruiting pro-caspase-1 to form the inflammasome [28]. The precursor of caspase-1 (pro-caspase-1) is activated after the assembly of the inflammasome and is hydrolyzed into two fragments to form a dimer and become mature caspase-1 [33]. On the one hand, the mature caspase-1 can cleave the executive protein GSDMD at Asp275 to form the 22kDa C-terminal repressor domain (RD) and the 32kDa pore-forming domain (PFD). Then, the N-terminal PFD oligomerizes and penetrates the cell membrane, forming non-selective pores with pore sizes of about 18 nm [34]; the ensuing increase in osmotic pressure then causes an influx of water followed by cell swelling and the release of cytokines and various cytoplasmic contents. On the other hand, the mature caspase-1 also lyses the precursors of IL-1β and IL-18 (pro-ILβ and pro-IL-18, respectively) to form mature IL-1β and IL-18, which are then released through holes formed by the N-terminal PFD and lead to cell pyroptosis [35]. However, it is worth noting that a recent study examined the cryo-electron microscopy structures of the pore and the prepore of GSDMD. The research revealed the different conformations of the two states and indicated that gasdermin D-mediated pores may not be non-selective and may favor the passage of IL-1β and IL-18 over that of their precursors [36]. Of course, further studies are needed to verify the selectivity or non-selectivity of gasdermin D-mediated pores.

3.2. Non-Canonical Pathway

Unlike the canonical pathway, human caspase-4/5 and mouse caspase-11 can directly bind to bacterial lipopolysaccharides (LPSs), thus bypassing the need for inflammasome sensors and resulting in cell pyroptosis [37]. Similar to mature caspase-1, activated caspase-4/5 or caspase-11 can also cleave GSDMD, thus releasing the N-terminal PFD. Then, the oligomerized N-terminal PFD is transferred to the cell membrane, leading to the formation of cell membrane pores [38]. The disruption of osmotic balance results in the release of cell contents and cell swelling and bursting, ultimately leading to cell pyroptosis. In addition, activated caspase-11 can not only promote K+ efflux through the induction of GSDMD cell membrane pore formation, but it can also activate the pannexin-1/ATP/P2 × 7 pathway by cleaving the pannexin-1 channel, releasing ATP, and activating the P2X7 receptor to cause ATP-induced loss of intracellular K+ and NLRP3 inflammasome activation. Once the NLRP3 inflammasome is assembled, the canonical pyroptosis pathways can be activated. Although caspase-4/5/11 cannot cleave pro-IL-1β or pro-IL-18 by themself, they can activate the pannexin-1/ATP/P2X7 pathway, thus leading to the activation of the canonical NLRP3/caspase-1 pathway and the ensuing maturation and secretion of IL-1β/IL-18 [39,40,41,42].

3.3. Caspase-3/8-Mediated Pathway

Caspase-3 has previously been considered as a marker and key molecule of apoptosis, but many studies have shown that caspase-3 is also involved in the process of pyroptosis. Under the stimulation of tumor necrosis factor-α (TNF-α) or chemotherapy drugs, caspase-3 has been shown to specifically cleave gasdermin E (GSDME), thus releasing the N-terminal PFD of GSDME [43]. The oligomerized N-terminal PFD of GSDME is then transferred to the cell membrane, forming non-selective pores and inducing cell pyroptosis. In addition, it is intriguing to note that activated caspase-3 would induce cell pyroptosis when the GSDME expression level was high, while activated caspase-3 would induce cell apoptosis when the GSDME expression level was low [19]. Moreover, it has been found that pathogenic Yersinia can inhibit TGF (transforming growth factor)-β-activated kinase 1 (TAK1) in mouse macrophages via the effector protein YopJ. As a result, receptor-interacting protein kinase 1 (RIPK1) and caspase-8 are activated. Subsequently, caspase-8 cleaves GSDMD and GSDME, forming the “gasdermin channel” on the plasma membrane that mediates pyroptosis and exacerbates the inflammatory response [44,45].

3.4. Granzyme-Mediated Pathway

A 2020 study found that CAR T cells could activate caspase-3 in target cells by releasing granzyme B (GzmB), thus activating the caspase-3/GSDME-mediated pyroptotic pathway [46]. Later, it was proven that GzmB can directly cleave GSDME and induce pyroptosis [47]. Meanwhile, it was also reported that natural killer cells and cytotoxic T lymphocytes killed GSDMB-positive cells by pyroptosis. The killing effect stemmed from GSDMB cleavage at the Lys229/Lys244 site by lymphocyte-derived granzyme A (GzmA) [48]. This was the first study to show that gasdermin could be hydrolyzed at non-aspartic acid sites and form pores, overturning the former understanding that pyroptosis can only be activated by caspases.

4. Pyroptosis and I/R Injury

I/R injury mainly revolves around various kinds of cell death and subsequent organ dysfunction. Previous studies have identified that necrosis, apoptosis, and autophagy-associated cell death are implicated in I/R injury [1]. Consequently, treatments targeted at these cell death patterns have also been investigated. Though some progress has been made in dealing with I/R injury so far, the outcomes are still far from satisfactory. Fortunately, the discovery of pyroptosis has brought new hope and impetus to the treatment of I/R injury, as an increasing number of studies have suggested that pyroptosis is involved in I/R injury (the link between pyroptosis and I/R injury was shown in Figure 2). This could allow the adoption of potentially feasible and effective approaches to alleviating I/R injury by targeting pyroptotic cell death. This section discusses the role of pyroptosis in I/R injury in different organs and possible therapeutic strategies to attenuate the intensity of I/R injury.

4.1. Pyroptosis and Cerebral I/R Injury

Cerebral artery occlusion is one of the main causes of ischemic strokes, and reperfusion is the best method to restore blood supply to cerebral ischemia and protect the brain from ischemic injury. However, reperfusion may cause more severe secondary injury to brain tissue, which is known as cerebral I/R injury. In 2019, a study conducted by Zhang et al. demonstrated that pyroptosis was involved in cerebral I/R injury, with gasdermin D acting as the key executor of pyroptosis in their model [49]. In 2020, Sun Rui et al. established an ischemic stroke mouse model via middle cerebral artery occlusion [50]. At the same time, the primary cortical neurons were extracted and cultured, and oxygen–glucose deprivation was used to establish an in vitro model. Their study showed that a low-density lipoprotein receptor (LDLR) inhibits neuronal death after cerebral I/R injury by inhibiting NLRP3-mediated neuronal pyroptosis. Similarly, other studies have also shown that hispidulin, glycosides, remimazolam, and dendrobium alkaloids can all exert neuroprotective effects in the event of cerebral I/R injury by inhibiting NLRP3-mediated pyroptosis [51,52,53,54]. In addition, it has been reported that valproic acid and overexpression of CHRFAM7A as well as down-regulation of X-box binding protein l (XBP-1) can also alleviate cerebral I/R injury by inhibiting the caspase-1-mediated canonical pathway of pyroptosis [55,56,57].
Meanwhile, microRNAs are a class of small non-coding RNAs that play a significant role in various biological processes related to cell death. A recent study has suggested that microRNA-124 inhibits pyroptosis induced by cerebral I/R injury by regulating the STAT3 signaling pathway [58]. Furthermore, it has been suggested that ginsenoside Rd could attenuate cerebral I/R injury by exerting an anti-pyroptotic effect via the miR-139-5p/Keap1/Nrf2 axis [59]. Moreover, exosomes are small vesicles containing complex RNAs and proteins involved in cell-to-cell communication; a study indicated that exosomes derived from bone marrow mesenchymal stem cells attenuate cerebral I/R injury-induced neuroinflammation and pyroptosis by modulating microglia M1/M2 phenotypes [60]. Additionally, salvianolic acid injection also alleviates cerebral I/R injury by regulating the M1/M2 phenotypes of microglia and inhibiting the NLRP3 inflammasome/pyroptosis axis in microglia [61]. Finally, mircornA-29A in astrocyte-derived extracellular vesicles was found to inhibit cerebral I/R injury through TP53INP1 and the NF-κB/NLRP3 axis [62]. Here, it is worth noting that berberine also has a protective effect against neuron pyroptosis induced by cerebral I/R via inhibiting the NF-κB/NLRP3 pathway [63]. In addition to these drugs that can attenuate cerebral I/R injury, some researchers have even found that exercise and electroacupuncture can exert neuroprotective effects against cerebral I/R injury by alleviating inflammasome-induced pyroptosis [64,65]. While all the aforementioned studies focused on how to suppress cerebral I/R injury, some studies have focused on the opposite. For instance, Liang et al. found that the long non-coding RNA MEG3 can promote cerebral I/R injury by increasing pyroptosis via the targeting of the miR-485/AIM2 axis [66]. In a nutshell, these findings support the hypothesis that pyroptosis is involved in brain I/R injury and can be a new therapeutic target for treating cerebral I/R injury.

4.2. Pyroptosis and Myocardial I/R Injury

I/R injury is the most common pathological type of cardiovascular disease, which is often seen in heart transplantation, thrombolytic therapy, cardiopulmonary bypass surgery, and coronary artery bypass grafting. As early as 2017, it was found that cytoprotective activated protein C could avert NLRP3 inflammasome-induced myocardial I/R injury by inhibiting mammalian target of rapamycin complex 1 (mTORC1) [67]. In the same year, another study illuminated that pyroptosis mediated by the activation of the NLRP3 inflammomere aggravated myocardial I/R injury in diabetic rats [68]. In addition, it was also reported that calpain silencing inhibits the activation of the canonical pyroptotic pathway (NLRP3/ASC/caspase-1) and reduces myocardial I/R injury in mice [69]. Furthermore, Ye et al. also illustrated that emodin could alleviate gasdermin D-mediated myocardial I/R injury by inhibiting the TLR4/MyD88/NF-κB/NLRP3 inflammasome pathway [70]. Moreover, Ding et al. reported that by inhibiting microRNA-29A, SIRT can be targeted to inhibit oxidative stress and NLRP3-mediated pyroptosis to alleviate myocardial I/R injury [71]. Similarly, by down-regulating microRNA-29B, dexmedetomidine is able to inhibit cell pyroptosis caused by myocardial I/R injury in rats [72]. Furthermore, Dai et al. demonstrated that M2 macrophage-derived exosomes carry microRNA-148A to inhibit the TXNIP and TLR4/NF-κB/NLRP3 signaling pathways, thereby alleviating myocardial I/R injury [73]. Liu et al. illustrated that cardiac fibroblast-derived exosomes carry microRNA-133A to suppress cardiomyocyte pyroptosis in myocardial I/R injury, and Zhang et al. indicated that hypoxic cardiac microvascular endothelial cell-derived exosomes carry microRNA-27b-3p to alleviate myocardial I/R Injury via the Foxo1/GSDMD signaling pathway [74,75]. Similar to their functions in cerebral I/R injury, the exosomes of mesenchymal stem cells can also mitigate myocardial I/R injury through inhibiting the canonical pathway of pyroptosis [76,77]. In addition, by targeting the Akt/GSK3β/NF-κB pathway, aesculin can inhibit NLRP3 inflammasome-mediated pyroptosis and thereby attenuate myocardial I/R injury [78]. Apart from the aforementioned drugs, ethyl acetate extract of cinnamomi ramulus, cinnamic acid, igramomod, piperazine ferulate, sevoflurane, trimetazidine, tubastatin, geniposide, intracellular ion channel inositol 1,4,5-triphosphate receptor (IP3R1), and a soluble receptor for late glycation end products have all been found to have protective effects against myocardial I/R injury [79,80,81,82,83,84,85,86,87,88]. Additionally, sweroside can also protect against myocardial I/R injury partly by regulating the Keap1/Nrf2/NLRP3 axis to inhibit oxidative stress and pyroptosis [89]. However, both aquaporin 4 and uric acid can aggravate myocardial I/R injury via NLRP3 inflammasome-mediated pyroptosis [90,91]. Moreover, the circRNA circ-NNT promoted myocardial I/R injury through activating pyroptosis by sponging miR-33a-5p and regulating ubiquitin-specific protease-46 (USP46) expression [92]. In addition, it has been proven that methyltransferase-like protein 3 (METTL3) can aggravate myocardial I/R injury via facilitating DGCR8 binding to pri-miR-143-3p through m6A modification, thus enhancing miR-143-3p expression to suppress protein kinase C epsilon transcription and further exacerbate cardiomyocyte pyroptosis [93]. Therefore, targeting myocardial pyroptosis may provide a new therapeutic strategy for patients with cardiovascular recanalization as well as heart transplant recipients.

4.3. Pyroptosis and Renal I/R Injury

The earliest study on pyroptosis and renal I/R injury, which can be traced back to 2014, found that renal I/R injury can trigger the pyroptosis of renal tubule epithelial cells through the CHOP-caspase-11 pathway [94]. Although it had not yet been confirmed that the gasdermin family was the executor of pyroptosis at that time, this study found that levels of pyroptosis-related proteins, including caspase-1, caspase-11, and IL-1, were significantly increased after renal I/R injury. In 2019, enhancer of zeste homolog 2 was found to be able to block nox4-dependent ROS production through the ALK5/SMad2/3 signaling pathway both in vitro and in mouse renal I/R injury models, thus inhibiting the canonical pyroptotic pathway of renal cells and attenuating renal I/R injury [95]. In the same year, Tajima et al. found that b-hydroxybutyrate can also mitigate renal I/R injury through its anti-pyroptotic effects [96]. In addition, Diao et al. suggested that inhibition of PRMT5 can activate the Nrf2/HO-1 signaling pathway and attenuate oxidative stress-induced pyroptosis in a mouse renal I/R injury model [97]. Similarly, it has been reported that by targeting the Nrf2 pathway, salvianolic acid B can also modulate caspase-1-mediated pyroptosis, thus alleviating renal I/R injury [98]. However, Xiao et al. indicated that the transcript induced in spermiogenesis 40 (Tisp40) had quite the opposite effect, inducing tubular epithelial cell GSDMD-mediated pyroptosis in renal I/R injury via NF-κB signaling [99]. By contrast, cholecalciferol pretreatment can protect renal function in I/R-induced GSDMD-mediated acute kidney injury through inhibiting NF-κB activation and reducing ROS production [100]. In addition, it seems that microRNA is also involved in renal I/R injury. Wang et al. identified microRNA-92a-3p as an essential regulator of tubular epithelial cell pyroptosis during renal I/R injury by targeting the Nrf1/HO-1 signaling pathway [101]. Furthermore, unlike aquaporin 4, which is involved in myocardial I/R injury, it is aquaporin 2 that is involved in renal I/R injury. Additionally, it has been illuminated that overexpression of aquaporin 2 can lighten the extent of pyroptosis of renal tubular epithelial cells during renal I/R injury [102]. While all of the aforementioned studies indicated that GSDMD acted as an executor and contributor to renal I/R injury, a recent study by Tonnus et al. found that GSDMD-deficient mice are hypersensitive to I/R-induced acute kidney injury (AKI) and demonstrated that GSDMD functioned as a suppressor of I/R-induced AKI through a previously unknown non-cell autonomous crosstalk to necroptosis [103]. Nonetheless, all these results shed light on the role of pyroptosis in renal I/R injury and may provide new insights into the treatment of renal I/R injury.

4.4. Pyroptosis and Hepatic I/R Injury

Liver I/R injury usually occurs during liver resection and liver transplantation, and it is the main cause of graft dysfunction and liver failure after liver transplantation. A study conducted by Li et al. suggested that DHA alleviates hepatic I/R injury by activating the PI3K/Akt pathway and subsequently inhibiting the canonical pyroptotic pathway [104]. Similarly, N-acetyl-1-tryptophan can lighten hepatic I/R injury via inhibiting the TLR4/NLRP3/caspase-1 signaling pathway [105]. Moreover, hepatic I/R injury was attenuated in caspase-1/caspase-11 double-gene knockout mice, suggesting that apart from the canonical pyroptotic pathway, the non-canonical pathway of pyroptosis is also involved in liver I/R injury [106]. Hua et al. reported that glycyrrhizin can suppress GSDMD-mediated pyroptosis of Kupffer cells to alleviate hepatic I/R injury [107]. Also targeting the pyroptosis of Kupffer cells, Wang et al. found that carbon monoxide-releasing molecule-3 could inhibit Kupffer cell pyroptosis via the sGC-cGMP signaling pathway to alleviate hepatic ischemia-reperfusion injury [108]. In addition, in steatotic livers, I/R injury induces pyroptosis and aggravates hepatic injury through caspase-1 activation [109]. Furthermore, it has been suggested that the stimulator of interferon genes (STING) could exacerbate liver I/R injury by facilitating calcium-dependent caspase-1-GSDMD processing in macrophages [110]. Finally, Alaa et al. found that the application of octreopeptide and melatonin can reduce inflammasome-induced pyroptosis by the iTLR4-NF-κB-NLRP3 pathway, thus attenuating hepatic I/R injury [111]. These results suggest that the canonical and non-canonical pathways of pyroptosis can be used as potential therapeutic targets for liver I/R injury.

4.5. Pyroptosis and Other I/R Injuries

Jia et al. established that metformin can protect against intestinal I/R injury and cell pyroptosis via the TXNIP-NLRP3-GSDMD pathway [112]. In the visual organ, the long noncoding RNA H19 is involved in initiating the pyroptosis of retinal microglia caused by retinal I/R injury, suggesting that pyroptosis also exists in retinal I/R injury [113]. In the respiratory organ, pretreatment with recombinant high-mobility group box 1 protein (rHMGB1) inhibited pyroptosis of alveolar macrophages through the Keap1/Nrf2/HO-1 signaling pathway, thus fighting against lung I/R injury [114]. In addition, it has been suggested that matrix metallopeptidase 2 (MMP2) and matrix metallopeptidase 9 (MMP9) contribute to lung I/R injury via the promotion of lung pyroptosis [115]. In summary, all the above results provide new insights into inhibiting pyroptosis in the treatment of I/R injury in these organs.

5. Conclusions and Perspective

In the past few decades, the treatments for various types of I/R injury have been far from satisfactory, and one of the main reasons lies in the complexity of the types of cell death, which include apoptosis, necrosis, autophagy, and the newly uncovered ferroptosis and pyroptosis [116]. Although it has been confirmed that pyroptosis is involved in the I/R injury of various organs, whether it is a major contributor to the I/R injury of any specific organ remains to be determined. Because different cell death types are not completely isolated and may have a synergistic effect on the progression of I/R injury [117], future studies exploring the interactions between different types of cell death and identifying medicines that could simultaneously regulate multiple targets are urgently required. In this context, for instance, Yu et al. reported that the Shexiang Baoxin Pill (SBP) could mitigate myocardial I/R injury by interfering with autophagy and inhibiting myocardial pyroptosis at the same time [118]. Given the fact that caspase-3 plays a pivotal role both in apoptosis and GSDME-mediated pyroptosis, it is reasonable to deduce that there must be some interaction between pyroptosis and apoptosis during I/R injury. However, research investigating the relationship between pyroptosis and apoptosis with respect to I/R injury has remained extremely limited to date. Nonetheless, some researchers have recently developed the concept of PANoptosis in the study of infectious and inflammatory diseases, where pyroptosis, apoptosis, and necroptosis act together in a multimeric protein complex called a PANoptosome [119,120]. This allows all the components of PANoptosis to be regulated simultaneously. Thus, PANoptosis provides a new way to study the regulation of cell death in which different types of cell death may be simultaneously regulated. Furthermore, recent studies have shown that PANoptosis-like cell death occurs during retinal and cerebral I/R injury [121,122], which could lay a solid foundation for the discovery of effective medicines that could simultaneously inhibit pyroptosis, apoptosis, and necroptosis and substantially alleviate I/R injury. Here, it is worth noting that the protective function of the medicines described in this review are mostly limited to animals, and how these findings translate into clinical treatment is yet to be determined. In addition, the mechanisms of pyroptosis still need further investigation at present; other new pathways and factors regulating pyroptosis might also be unearthed in the future. In addition, yet-to-be discovered genes and pathways may yield novel treatment methods for I/R injury. It should also be noted that the discovery of key genes and pathways involved in I/R injury is far from enough and does not amount to better outcomes for the treatment of I/R injury, as these newly found genes and pathways might have a dual roles during I/R injury. For example, Zhang et al. discovered that although the knockout of GSDMD conferred resistance to the heart against reperfusion injury in the acute phase of I/R, the knockout of GSDMD exacerbated reperfusion injury in the chronic phase of I/R via the activation of PARylation and the consumption of NAD+ and ATP, thus resulting in cardiomyocyte apoptosis. This study thus indicated a multidirectional role of GSDMD in I/R injury and a correlation between apoptosis and pyroptosis [123].
In sum, pyroptosis, a newly uncovered type of regulated cell death, plays an important role in the pathogenesis of various I/R injuries and organ dysfunction. Suppressing pyroptosis could be an effective therapeutic method for I/R injury. However, understanding the mechanisms of pyroptosis still requires in-depth investigation. In the future, after the mechanisms underpinning pyroptosis and its interactions with other types of cell death are fully understood, combined therapy simultaneously regulating multiple pathways might be the most effective strategy for limiting the severity of I/R injury.

Author Contributions

Y.Z. and X.X. designed and wrote the review. F.C. revised the manuscript. N.C. revised the contents of the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by grants from the National Natural Science Foundation of China (Nos. 81970889 and 81420108010 to F.C.) and the Science and Technology Committee of Shanghai (grant number 22S31903100 to F.C.).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Eltzschig, H.K.; Eckle, T. Ischemia and reperfusion—From mechanism to translation. Nat. Med. 2011, 17, 1391–1401. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Lamkanfi, M.; Dixit, V.M. Mechanisms and functions of inflammasomes. Cell 2014, 157, 1013–1022. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Yu, P.; Zhang, X.; Liu, N.; Tang, L.; Peng, C.; Chen, X. Pyroptosis: Mechanisms and diseases. Signal Transduct. Target. Ther. 2021, 6, 128. [Google Scholar] [CrossRef] [PubMed]
  4. Pantazi, E.; Bejaoui, M.; Folch-Puy, E.; Adam, R.; Rosello-Catafau, J. Advances in treatment strategies for ischemia reperfusion injury. Expert Opin. Pharmacother. 2016, 17, 169–179. [Google Scholar] [CrossRef] [Green Version]
  5. Zychlinsky, A.; Prevost, M.C.; Sansonetti, P.J. Shigella flexneri induces apoptosis in infected macrophages. Nature 1992, 358, 167–169. [Google Scholar] [CrossRef]
  6. Chen, Y.; Smith, M.R.; Thirumalai, K.; Zychlinsky, A. A bacterial invasin induces macrophage apoptosis by binding directly to ICE. EMBO J. 1996, 15, 3853–3860. [Google Scholar] [CrossRef]
  7. Hersh, D.; Monack, D.M.; Smith, M.R.; Ghori, N.; Falkow, S.; Zychlinsky, A. The Salmonella invasin SipB induces macrophage apoptosis by binding to caspase-1. Proc. Natl. Acad. Sci. USA 1999, 96, 2396–2401. [Google Scholar] [CrossRef] [Green Version]
  8. Brennan, M.A.; Cookson, B.T. Salmonella induces macrophage death by caspase-1-dependent necrosis. Mol. Microbiol. 2000, 38, 31–40. [Google Scholar] [CrossRef] [Green Version]
  9. Fink, S.L.; Bergsbaken, T.; Cookson, B.T. Anthrax lethal toxin and Salmonella elicit the common cell death pathway of caspase-1-dependent pyroptosis via distinct mechanisms. Proc. Natl. Acad. Sci. USA 2008, 105, 4312–4317. [Google Scholar] [CrossRef] [Green Version]
  10. Kayagaki, N.; Warming, S.; Lamkanfi, M.; Vande, W.L.; Louie, S.; Dong, J.; Newton, K.; Qu, Y.; Liu, J.; Heldens, S.; et al. Non-canonical inflammasome activation targets caspase-11. Nature 2011, 479, 117–121. [Google Scholar] [CrossRef]
  11. Shi, J.; Zhao, Y.; Wang, K.; Shi, X.; Wang, Y.; Huang, H.; Zhuang, Y.; Cai, T.; Wang, F.; Shao, F. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 2015, 526, 660–665. [Google Scholar] [CrossRef] [PubMed]
  12. Ding, J.; Wang, K.; Liu, W.; She, Y.; Sun, Q.; Shi, J.; Sun, H.; Wang, D.C.; Shao, F. Pore-forming activity and structural autoinhibition of the gasdermin family. Nature 2016, 535, 111–116. [Google Scholar] [CrossRef] [PubMed]
  13. He, W.T.; Wan, H.; Hu, L.; Chen, P.; Wang, X.; Huang, Z.; Yang, Z.H.; Zhong, C.Q.; Han, J. Gasdermin D is an executor of pyroptosis and required for interleukin-1beta secretion. Cell Res. 2015, 25, 1285–1298. [Google Scholar] [CrossRef] [PubMed]
  14. Yu, J.; Nagasu, H.; Murakami, T.; Hoang, H.; Broderick, L.; Hoffman, H.M.; Horng, T. Inflammasome activation leads to Caspase-1-dependent mitochondrial damage and block of mitophagy. Proc. Natl. Acad. Sci. USA 2014, 111, 15514–15519. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Bergsbaken, T.; Fink, S.L.; den Hartigh, A.B.; Loomis, W.P.; Cookson, B.T. Coordinated host responses during pyroptosis: Caspase-1-dependent lysosome exocytosis and inflammatory cytokine maturation. J. Immunol. 2011, 187, 2748–2754. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Rogers, C.; Erkes, D.A.; Nardone, A.; Aplin, A.E.; Fernandes-Alnemri, T.; Alnemri, E.S. Gasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation. Nat. Commun. 2019, 10, 1689. [Google Scholar] [CrossRef] [Green Version]
  17. Liu, Z.; Wang, C.; Yang, J.; Zhou, B.; Yang, R.; Ramachandran, R.; Abbott, D.W.; Xiao, T.S. Crystal Structures of the Full-Length Murine and Human Gasdermin D Reveal Mechanisms of Autoinhibition, Lipid Binding, and Oligomerization. Immunity 2019, 51, 43–49. [Google Scholar] [CrossRef]
  18. Kuang, S.; Zheng, J.; Yang, H.; Li, S.; Duan, S.; Shen, Y.; Ji, C.; Gan, J.; Xu, X.W.; Li, J. Structure insight of GSDMD reveals the basis of GSDMD autoinhibition in cell pyroptosis. Proc. Natl. Acad. Sci USA 2017, 114, 10642–10647. [Google Scholar] [CrossRef] [Green Version]
  19. Rogers, C.; Fernandes-Alnemri, T.; Mayes, L.; Alnemri, D.; Cingolani, G.; Alnemri, E.S. Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death. Nat. Commun. 2017, 8, 14128. [Google Scholar] [CrossRef] [Green Version]
  20. Kayagaki, N.; Stowe, I.B.; Lee, B.L.; O’Rourke, K.; Anderson, K.; Warming, S.; Cuellar, T.; Haley, B.; Roose-Girma, M.; Phung, Q.T.; et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 2015, 526, 666–671. [Google Scholar] [CrossRef]
  21. Aglietti, R.A.; Dueber, E.C. Recent Insights into the Molecular Mechanisms Underlying Pyroptosis and Gasdermin Family Functions. Trends Immunol. 2017, 38, 261–271. [Google Scholar] [CrossRef] [PubMed]
  22. Liu, X.; Zhang, Z.; Ruan, J.; Pan, Y.; Magupalli, V.G.; Wu, H.; Lieberman, J. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 2016, 535, 153–158. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Liston, A.; Masters, S.L. Homeostasis-altering molecular processes as mechanisms of inflammasome activation. Nat. Rev. Immunol. 2017, 17, 208–214. [Google Scholar] [CrossRef]
  24. Strowig, T.; Henao-Mejia, J.; Elinav, E.; Flavell, R. Inflammasomes in health and disease. Nature 2012, 481, 278–286. [Google Scholar] [CrossRef] [PubMed]
  25. Jorgensen, I.; Zhang, Y.; Krantz, B.A.; Miao, E.A. Pyroptosis triggers pore-induced intracellular traps (PITs) that capture bacteria and lead to their clearance by efferocytosis. J. Exp. Med. 2016, 213, 2113–2128. [Google Scholar] [CrossRef] [Green Version]
  26. Levy, M.; Thaiss, C.A.; Zeevi, D.; Dohnalova, L.; Zilberman-Schapira, G.; Mahdi, J.A.; David, E.; Savidor, A.; Korem, T.; Herzig, Y.; et al. Microbiota-Modulated Metabolites Shape the Intestinal Microenvironment by Regulating NLRP6 Inflammasome Signaling. Cell 2015, 163, 1428–1443. [Google Scholar] [CrossRef] [Green Version]
  27. Martinon, F.; Burns, K.; Tschopp, J. The inflammasome: A molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol. Cell 2002, 10, 417–426. [Google Scholar] [CrossRef]
  28. Broz, P.; Dixit, V.M. Inflammasomes: Mechanism of assembly, regulation and signalling. Nat. Rev. Immunol. 2016, 16, 407–420. [Google Scholar] [CrossRef]
  29. Zitvogel, L.; Kepp, O.; Galluzzi, L.; Kroemer, G. Inflammasomes in carcinogenesis and anticancer immune responses. Nat. Immunol. 2012, 13, 343–351. [Google Scholar] [CrossRef]
  30. Lamkanfi, M. Emerging inflammasome effector mechanisms. Nat. Rev. Immunol. 2011, 11, 213–220. [Google Scholar] [CrossRef]
  31. Kawai, T.; Akira, S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 2011, 34, 637–650. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Barton, G.M.; Medzhitov, R. Toll-like receptor signaling pathways. Science 2003, 300, 1524–1525. [Google Scholar] [CrossRef] [PubMed]
  33. Sollberger, G.; Strittmatter, G.E.; Garstkiewicz, M.; Sand, J.; Beer, H.D. Caspase-1: The inflammasome and beyond. Innate Immun. 2014, 20, 115–125. [Google Scholar] [CrossRef] [Green Version]
  34. Sborgi, L.; Ruhl, S.; Mulvihill, E.; Pipercevic, J.; Heilig, R.; Stahlberg, H.; Farady, C.J.; Muller, D.J.; Broz, P.; Hiller, S. GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death. EMBO J. 2016, 35, 1766–1778. [Google Scholar] [CrossRef] [PubMed]
  35. Bergsbaken, T.; Fink, S.L.; Cookson, B.T. Pyroptosis: Host cell death and inflammation. Nat. Rev. Microbiol. 2009, 7, 99–109. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Xia, S.; Zhang, Z.; Magupalli, V.G.; Pablo, J.L.; Dong, Y.; Vora, S.M.; Wang, L.; Fu, T.M.; Jacobson, M.P.; Greka, A.; et al. Gasdermin D pore structure reveals preferential release of mature interleukin-1. Nature 2021, 593, 607–611. [Google Scholar] [CrossRef]
  37. Shi, J.; Zhao, Y.; Wang, Y.; Gao, W.; Ding, J.; Li, P.; Hu, L.; Shao, F. Inflammatory caspases are innate immune receptors for intracellular LPS. Nature 2014, 514, 187–192. [Google Scholar] [CrossRef]
  38. Aglietti, R.A.; Estevez, A.; Gupta, A.; Ramirez, M.G.; Liu, P.S.; Kayagaki, N.; Ciferri, C.; Dixit, V.M.; Dueber, E.C. GsdmD p30 elicited by caspase-11 during pyroptosis forms pores in membranes. Proc. Natl. Acad. Sci. USA 2016, 113, 7858–7863. [Google Scholar] [CrossRef] [Green Version]
  39. Baker, P.J.; Boucher, D.; Bierschenk, D.; Tebartz, C.; Whitney, P.G.; D’Silva, D.B.; Tanzer, M.C.; Monteleone, M.; Robertson, A.A.; Cooper, M.A.; et al. NLRP3 inflammasome activation downstream of cytoplasmic LPS recognition by both caspase-4 and caspase-5. Eur. J. Immunol. 2015, 45, 2918–2926. [Google Scholar] [CrossRef]
  40. Ruhl, S.; Broz, P. Caspase-11 activates a canonical NLRP3 inflammasome by promoting K(+) efflux. Eur. J. Immunol. 2015, 45, 2927–2936. [Google Scholar] [CrossRef]
  41. Schmid-Burgk, J.L.; Gaidt, M.M.; Schmidt, T.; Ebert, T.S.; Bartok, E.; Hornung, V. Caspase-4 mediates non-canonical activation of the NLRP3 inflammasome in human myeloid cells. Eur. J. Immunol. 2015, 45, 2911–2917. [Google Scholar] [CrossRef] [PubMed]
  42. Yang, D.; He, Y.; Munoz-Planillo, R.; Liu, Q.; Nunez, G. Caspase-11 Requires the Pannexin-1 Channel and the Purinergic P2X7 Pore to Mediate Pyroptosis and Endotoxic Shock. Immunity 2015, 43, 923–932. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Wang, Y.; Gao, W.; Shi, X.; Ding, J.; Liu, W.; He, H.; Wang, K.; Shao, F. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature 2017, 547, 99–103. [Google Scholar] [CrossRef]
  44. Orning, P.; Weng, D.; Starheim, K.; Ratner, D.; Best, Z.; Lee, B.; Brooks, A.; Xia, S.; Wu, H.; Kelliher, M.A.; et al. Pathogen blockade of TAK1 triggers caspase-8-dependent cleavage of gasdermin D and cell death. Science 2018, 362, 1064–1069. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Sarhan, J.; Liu, B.C.; Muendlein, H.I.; Li, P.; Nilson, R.; Tang, A.Y.; Rongvaux, A.; Bunnell, S.C.; Shao, F.; Green, D.R.; et al. Caspase-8 induces cleavage of gasdermin D to elicit pyroptosis during Yersinia infection. Proc. Natl. Acad. Sci. USA 2018, 115, E10888–E10897. [Google Scholar] [CrossRef] [Green Version]
  46. Liu, Y.; Fang, Y.; Chen, X.; Wang, Z.; Liang, X.; Zhang, T.; Liu, M.; Zhou, N.; Lv, J.; Tang, K.; et al. Gasdermin E-mediated target cell pyroptosis by CAR T cells triggers cytokine release syndrome. Sci. Immunol. 2020, 5, eaax7969. [Google Scholar] [CrossRef]
  47. Zhang, Z.; Zhang, Y.; Xia, S.; Kong, Q.; Li, S.; Liu, X.; Junqueira, C.; Meza-Sosa, K.F.; Mok, T.; Ansara, J.; et al. Gasdermin E suppresses tumour growth by activating anti-tumour immunity. Nature 2020, 579, 415–420. [Google Scholar] [CrossRef]
  48. Zhou, Z.; He, H.; Wang, K.; Shi, X.; Wang, Y.; Su, Y.; Wang, Y.; Li, D.; Liu, W.; Zhang, Y.; et al. Granzyme A from cytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells. Science 2020, 368, 6494. [Google Scholar] [CrossRef]
  49. Zhang, D.; Qian, J.; Zhang, P.; Li, H.; Shen, H.; Li, X.; Chen, G. Gasdermin D serves as a key executioner of pyroptosis in experimental cerebral ischemia and reperfusion model both in vivo and in vitro. J. Neurosci. Res. 2019, 97, 645–660. [Google Scholar] [CrossRef]
  50. Sun, R.; Peng, M.; Xu, P.; Huang, F.; Xie, Y.; Li, J.; Hong, Y.; Guo, H.; Liu, Q.; Zhu, W. Low-density lipoprotein receptor (LDLR) regulates NLRP3-mediated neuronal pyroptosis following cerebral ischemia/reperfusion injury. J. Neuroinflammation 2020, 17, 330. [Google Scholar] [CrossRef]
  51. Liu, D.; Dong, Z.; Xiang, F.; Liu, H.; Wang, Y.; Wang, Q.; Rao, J. Dendrobium Alkaloids Promote Neural Function After Cerebral Ischemia–Reperfusion Injury Through Inhibiting Pyroptosis Induced Neuronal Death in both In Vivo and In Vitro Models. Neurochem. Res. 2020, 45, 437–454. [Google Scholar] [CrossRef] [PubMed]
  52. An, P.; Xie, J.; Qiu, S.; Liu, Y.; Wang, J.; Xiu, X.; Li, L.; Tang, M. Hispidulin exhibits neuroprotective activities against cerebral ischemia reperfusion injury through suppressing NLRP3-mediated pyroptosis. Life Sci. 2019, 232, 116599. [Google Scholar] [CrossRef] [PubMed]
  53. She, Y.; Shao, L.; Zhang, Y.; Hao, Y.; Cai, Y.; Cheng, Z.; Deng, C.; Liu, X. Neuroprotective effect of glycosides in Buyang Huanwu Decoction on pyroptosis following cerebral ischemia-reperfusion injury in rats. J. Ethnopharmacol. 2019, 242, 112051. [Google Scholar] [CrossRef] [PubMed]
  54. Shi, M.; Chen, J.; Liu, T.; Dai, W.; Zhou, Z.; Chen, L.; Xie, Y. Protective Effects of Remimazolam on Cerebral Ischemia/Reperfusion Injury in Rats by Inhibiting of NLRP3 Inflammasome-Dependent Pyroptosis. Drug Des. Dev. Ther. 2022, 16, 413–423. [Google Scholar] [CrossRef]
  55. Cao, X.; Wang, Y.; Gao, L. CHRFAM7A Overexpression Attenuates Cerebral Ischemia-Reperfusion Injury via Inhibiting Microglia Pyroptosis Mediated by the NLRP3/Caspase-1 pathway. Inflammation 2021, 44, 1023–1034. [Google Scholar] [CrossRef]
  56. Zhu, S.; Zhang, Z.; Jia, L.; Zhan, K.; Wang, L.; Song, N.; Liu, Y.; Cheng, Y.; Yang, Y.; Guan, L.; et al. Valproic acid attenuates global cerebral ischemia/reperfusion injury in gerbils via anti-pyroptosis pathways. Neurochem. Int. 2019, 124, 141–151. [Google Scholar] [CrossRef]
  57. Zhang, Y.; Yao, Z.; Xiao, Y.; Zhang, X.; Liu, J. Downregulated XBP-1 Rescues Cerebral Ischemia/Reperfusion Injury-Induced Pyroptosis via the NLRP3/Caspase-1/GSDMD Axis. Mediat. Inflamm. 2022, 2022, 8007078. [Google Scholar] [CrossRef]
  58. Sun, H.; Li, J.J.; Feng, Z.R.; Liu, H.Y.; Meng, A.G. MicroRNA-124 regulates cell pyroptosis during cerebral ischemia-reperfusion injury by regulating STAT3. Exp. Ther. Med. 2020, 20, 227. [Google Scholar] [CrossRef]
  59. Yao, Y.; Hu, S.; Zhang, C.; Zhou, Q.; Wang, H.; Yang, Y.; Liu, C.; Ding, H. Ginsenoside Rd attenuates cerebral ischemia/reperfusion injury by exerting an anti-pyroptotic effect via the miR-139-5p/FoxO1/Keap1/Nrf2 axis. Int. Immunopharmacol. 2022, 105, 108582. [Google Scholar] [CrossRef]
  60. Liu, X.; Zhang, M.; Liu, H.; Zhu, R.; He, H.; Zhou, Y.; Zhang, Y.; Li, C.; Liang, D.; Zeng, Q.; et al. Bone marrow mesenchymal stem cell-derived exosomes attenuate cerebral ischemia-reperfusion injury-induced neuroinflammation and pyroptosis by modulating microglia M1/M2 phenotypes. Exp. Neurol. 2021, 341, 113700. [Google Scholar] [CrossRef]
  61. Ma, D.; Zhang, N.; Zhang, Y.; Chen, H. Salvianolic Acids for Injection alleviates cerebral ischemia/reperfusion injury by switching M1/M2 phenotypes and inhibiting NLRP3 inflammasome/pyroptosis axis in microglia in vivo and in vitro. J. Ethnopharmacol. 2021, 270, 113776. [Google Scholar] [CrossRef] [PubMed]
  62. Liu, X.; Lv, X.; Liu, Z.; Zhang, M.; Leng, Y. MircoRNA-29a in Astrocyte-derived Extracellular Vesicles Suppresses Brain Ischemia Reperfusion Injury via TP53INP1 and the NF-κB/NLRP3 Axis. Cell. Mol. Neurobiol. 2021, 42, 1487–1500. [Google Scholar] [CrossRef] [PubMed]
  63. Zhao, Y.; Li, Z.; Lu, E.; Sheng, Q.; Zhao, Y. Berberine exerts neuroprotective activities against cerebral ischemia/reperfusion injury through up-regulating PPAR-γ to suppress NF-κB-mediated pyroptosis. Brain Res. Bull. 2021, 177, 22–30. [Google Scholar] [CrossRef] [PubMed]
  64. Liu, M.; Luo, L.; Fu, J.; He, J.; Chen, M.; He, Z.; Jia, J. Exercise-induced neuroprotection against cerebral ischemia/reperfusion injury is mediated via alleviating inflammasome-induced pyroptosis. Exp. Neurol. 2022, 349, 113952. [Google Scholar] [CrossRef]
  65. Cai, L.; Yao, Z.; Yang, L.; Xu, X.; Luo, M.; Dong, M.; Zhou, G. Mechanism of Electroacupuncture Against Cerebral Ischemia–Reperfusion Injury: Reducing Inflammatory Response and Cell Pyroptosis by Inhibiting NLRP3 and Caspase-1. Front. Mol. Neurosci. 2022, 15, 822088. [Google Scholar] [CrossRef]
  66. Liang, J.; Wang, Q.; Li, J.; Guo, T.; Yu, D. Long non-coding RNA MEG3 promotes cerebral ischemia-reperfusion injury through increasing pyroptosis by targeting miR-485/AIM2 axis. Exp. Neurol. 2020, 325, 113139. [Google Scholar] [CrossRef]
  67. Nazir, S.; Gadi, I.; Al-Dabet, M.M.; Elwakiel, A.; Kohli, S.; Ghosh, S.; Manoharan, J.; Ranjan, S.; Bock, F.; Braun-Dullaeus, R.C.; et al. Cytoprotective activated protein C averts Nlrp3 inflammasome-induced ischemia-reperfusion injury via mTORC1 inhibition. Blood 2017, 130, 2664–2677. [Google Scholar] [CrossRef] [Green Version]
  68. Qiu, Z.; Lei, S.; Zhao, B.; Wu, Y.; Su, W.; Liu, M.; Meng, Q.; Zhou, B.; Leng, Y.; Xia, Z. NLRP3 Inflammasome Activation-Mediated Pyroptosis Aggravates Myocardial Ischemia/Reperfusion Injury in Diabetic Rats. Oxidative Med. Cell. Longev. 2017, 2017, 9743280. [Google Scholar] [CrossRef]
  69. Yue, R.; Lu, S.; Luo, Y.; Wang, T.; Liang, H.; Zeng, J.; Liu, J.; Hu, H. Calpain silencing alleviates myocardial ischemia-reperfusion injury through the NLRP3/ASC/Caspase-1 axis in mice. Life Sci. 2019, 233, 116631. [Google Scholar] [CrossRef]
  70. Ye, B.; Chen, X.; Dai, S.; Han, J.; Liang, X.; Lin, S.; Cai, X.; Huang, Z.; Huang, W. Emodin alleviates myocardial ischemia/reperfusion injury by inhibiting gasdermin D-mediated pyroptosis in cardiomyocytes. Drug Des. Dev. Ther. 2019, 13, 975–990. [Google Scholar] [CrossRef]
  71. Ding, S.; Liu, D.; Wang, L.; Wang, G.; Zhu, Y. Inhibiting MicroRNA-29a Protects Myocardial Ischemia-Reperfusion Injury by Targeting SIRT1 and Suppressing Oxidative Stress and NLRP3-Mediated Pyroptosis Pathway. J. Pharmacol. Exp. Ther. 2019, 372, 128–135. [Google Scholar] [CrossRef] [PubMed]
  72. Zhong, Y.; Li, Y.P.; Yin, Y.Q.; Hu, B.L.; Gao, H. Dexmedetomidine inhibits pyroptosis by down-regulating miR-29b in myocardial ischemia reperfusion injury in rats. Int. Immunopharmacol. 2020, 86, 106768. [Google Scholar] [CrossRef] [PubMed]
  73. Dai, Y.; Wang, S.; Chang, S.; Ren, D.; Shali, S.; Li, C.; Yang, H.; Huang, Z.; Ge, J. M2 macrophage-derived exosomes carry microRNA-148a to alleviate myocardial ischemia/reperfusion injury via inhibiting TXNIP and the TLR4/NF-κB/NLRP3 inflammasome signaling pathway. J. Mol. Cell. Cardiol. 2020, 142, 65–79. [Google Scholar] [CrossRef] [PubMed]
  74. Liu, N.; Xie, L.; Xiao, P.; Chen, X.; Kong, W.; Lou, Q.; Chen, F.; Lu, X. Cardiac fibroblasts secrete exosome microRNA to suppress cardiomyocyte pyroptosis in myocardial ischemia/reperfusion injury. Mol. Cell. Biochem. 2022, 477, 1249–1260. [Google Scholar] [CrossRef]
  75. Zhang, B.; Sun, C.; Liu, Y.; Bai, F.; Tu, T.; Liu, Q. Exosomal miR-27b-3p Derived from Hypoxic Cardiac Microvascular Endothelial Cells Alleviates Rat Myocardial Ischemia/Reperfusion Injury through Inhibiting Oxidative Stress-Induced Pyroptosis via Foxo1/GSDMD Signaling. Oxidative Med. Cell. Longev. 2022, 2022, 8215842. [Google Scholar] [CrossRef]
  76. Tang, J.; Jin, L.; Liu, Y.; Li, L.; Ma, Y.; Lu, L.; Ma, J.; Ding, P.; Yang, X.; Liu, J.; et al. Exosomes Derived from Mesenchymal Stem Cells Protect the Myocardium Against Ischemia/Reperfusion Injury Through Inhibiting Pyroptosis. Drug Des. Dev. Ther. 2020, 14, 3765–3775. [Google Scholar] [CrossRef]
  77. Yue, R.; Lu, S.; Luo, Y.; Zeng, J.; Liang, H.; Qin, D.; Wang, X.; Wang, T.; Pu, J.; Hu, H. Mesenchymal stem cell-derived exosomal microRNA-182-5p alleviates myocardial ischemia/reperfusion injury by targeting GSDMD in mice. Cell Death Discov. 2022, 8, 202. [Google Scholar] [CrossRef]
  78. Xu, X.; Jiang, Y.; Yan, L.; Yin, S.; Wang, Y.; Wang, S.; Fang, L.; Du, G. Aesculin suppresses the NLRP3 inflammasome-mediated pyroptosis via the Akt/GSK3β/NF-κB pathway to mitigate myocardial ischemia/reperfusion injury. Phytomedicine 2021, 92, 153687. [Google Scholar] [CrossRef]
  79. Peng, L.; Lei, Z.; Rao, Z.; Yang, R.; Zheng, L.; Fan, Y.; Luan, F.; Zeng, N. Cardioprotective activity of ethyl acetate extract of Cinnamomi Ramulus against myocardial ischemia/reperfusion injury in rats via inhibiting NLRP3 inflammasome activation and pyroptosis. Phytomedicine 2021, 93, 153798. [Google Scholar] [CrossRef]
  80. Zhang, M.; Lei, Y.S.; Meng, X.W.; Liu, H.Y.; Li, L.G.; Zhang, J.; Zhang, J.X.; Tao, W.H.; Peng, K.; Lin, J.; et al. Iguratimod Alleviates Myocardial Ischemia/Reperfusion Injury Through Inhibiting Inflammatory Response Induced by Cardiac Fibroblast Pyroptosis via COX2/NLRP3 Signaling Pathway. Front. Cell Dev. Biol. 2021, 9, 746317. [Google Scholar] [CrossRef]
  81. Liu, Y.; Guo, X.; Zhang, J.; Han, X.; Wang, H.; Du, F.; Zeng, X.; Guo, C. Protective Effects of the Soluble Receptor for Advanced Glycation End-Products on Pyroptosis during Myocardial Ischemia-Reperfusion. Oxidative Med. Cell. Longev. 2021, 2021, 9570971. [Google Scholar] [CrossRef] [PubMed]
  82. Wu, J.; Cai, W.; Du, R.; Li, H.; Wang, B.; Zhou, Y.; Shen, D.; Shen, H.; Lan, Y.; Chen, L.; et al. Sevoflurane Alleviates Myocardial Ischemia Reperfusion Injury by Inhibiting P2X7-NLRP3 Mediated Pyroptosis. Front. Mol. Biosci. 2021, 8, 768594. [Google Scholar] [CrossRef] [PubMed]
  83. Mo, G.; Liu, X.; Zhong, Y.; Mo, J.; Li, Z.; Li, D.; Zhang, L.; Liu, Y. IP3R1 regulates Ca2+ transport and pyroptosis through the NLRP3/Caspase-1 pathway in myocardial ischemia/reperfusion injury. Cell Death Discov. 2021, 7, 31. [Google Scholar] [CrossRef] [PubMed]
  84. Luan, F.; Rao, Z.; Peng, L.; Lei, Z.; Zeng, J.; Peng, X.; Yang, R.; Liu, R.; Zeng, N. Cinnamic acid preserves against myocardial ischemia/reperfusion injury via suppression of NLRP3/Caspase-1/GSDMD signaling pathway. Phytomedicine 2022, 100, 154047. [Google Scholar] [CrossRef]
  85. Lei, Z.; Luan, F.; Zhang, X.; Peng, L.; Li, B.; Peng, X.; Liu, Y.; Liu, R.; Zeng, N. Piperazine ferulate protects against cardiac ischemia/reperfusion injury in rat via the suppression of NLRP3 inflammasome activation and pyroptosis. Eur. J. Pharmacol. 2022, 920, 174856. [Google Scholar] [CrossRef]
  86. Chen, X.; Lin, S.; Dai, S.; Han, J.; Shan, P.; Wang, W.; Huang, Z.; Ye, B.; Huang, W. Trimetazidine affects pyroptosis by targeting GSDMD in myocardial ischemia/reperfusion injury. Inflamm. Res. 2022, 71, 227–241. [Google Scholar] [CrossRef]
  87. Xu, J.; Zhao, X.; Jiang, X.; He, L.; Wu, X.; Wang, J.; Chen, Q.; Li, Y.; Zhang, M. Tubastatin A Improves Post-Resuscitation Myocardial Dysfunction by Inhibiting NLRP3-Mediated Pyroptosis Through Enhancing Transcription Factor EB Signaling. J. Am. Heart Assoc. 2022, 11, e024205. [Google Scholar] [CrossRef]
  88. Li, H.; Yang, D.H.; Zhang, Y.; Zheng, F.; Gao, F.; Sun, J.; Shi, G. Geniposide suppresses NLRP3 inflammasome-mediated pyroptosis via the AMPK signaling pathway to mitigate myocardial ischemia/reperfusion injury. Chin. Med. 2022, 17, 73. [Google Scholar] [CrossRef]
  89. Li, J.; Zhao, C.; Zhu, Q.; Wang, Y.; Li, G.; Li, X.; Li, Y.; Wu, N.; Ma, C. Sweroside Protects Against Myocardial Ischemia–Reperfusion Injury by Inhibiting Oxidative Stress and Pyroptosis Partially via Modulation of the Keap1/Nrf2 Axis. Front. Cardiovasc. Med. 2021, 8, 650368. [Google Scholar] [CrossRef]
  90. Shen, S.; He, F.; Cheng, C.; Xu, B.; Sheng, J. Uric acid aggravates myocardial ischemia-reperfusion injury via ROS/NLRP3 pyroptosis pathway. Biomed. Pharmacother. 2021, 133, 110990. [Google Scholar] [CrossRef]
  91. Jiang, Q.; Dong, X.; Hu, D.; Chen, L.; Luo, Y. Aquaporin 4 inhibition alleviates myocardial ischemia-reperfusion injury by restraining cardiomyocyte pyroptosis. Bioengineered 2021, 12, 9021–9030. [Google Scholar] [CrossRef] [PubMed]
  92. Ye, X.; Hang, Y.; Lu, Y.; Li, D.; Shen, F.; Guan, P.; Dong, J.; Shi, L.; Hu, W. CircRNA circ-NNT mediates myocardial ischemia/reperfusion injury through activating pyroptosis by sponging miR-33a-5p and regulating USP46 expression. Cell Death Discov. 2021, 7, 370. [Google Scholar] [CrossRef] [PubMed]
  93. Wang, X.; Li, Y.; Li, J.; Li, S.; Wang, F. Mechanism of METTL3-Mediated m6A Modification in Cardiomyocyte Pyroptosis and Myocardial Ischemia–Reperfusion Injury. Cardiovasc. Drugs Ther. 2022, 1–14. [Google Scholar] [CrossRef]
  94. Yang, J.; Yao, F.; Zhang, J.; Ji, Z.; Li, K.; Zhan, J.; Tong, Y.; Lin, L.; He, Y. Ischemia-reperfusion induces renal tubule pyroptosis via the CHOP-caspase-11 pathway. Am. J. Physiol.-Ren. Physiol. 2014, 306, F75–F84. [Google Scholar] [CrossRef] [PubMed]
  95. Liu, H.; Chen, Z.; Weng, X.; Chen, H.; Du, Y.; Diao, C.; Liu, X.; Wang, L. Enhancer of zeste homolog 2 modulates oxidative stress—mediated pyroptosis in vitro and in a mouse kidney ischemia—reperfusion injury model. FASEB J. 2020, 34, 835–852. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  96. Tajima, T.; Yoshifuji, A.; Matsui, A.; Itoh, T.; Uchiyama, K.; Kanda, T.; Tokuyama, H.; Wakino, S.; Itoh, H. beta-hydroxybutyrate attenuates renal ischemia-reperfusion injury through its anti-pyroptotic effects. Kidney Int. 2019, 95, 1120–1137. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  97. Diao, C.; Chen, Z.; Qiu, T.; Liu, H.; Yang, Y.; Liu, X.; Wu, J.; Wang, L. Inhibition of PRMT5 Attenuates Oxidative Stress-Induced Pyroptosis via Activation of the Nrf2/HO-1 Signal Pathway in a Mouse Model of Renal Ischemia-Reperfusion Injury. Oxidative Med. Cell. Longev. 2019, 2019, 2345658. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  98. Pang, Y.; Zhang, P.; Lu, R.; Li, H.; Li, J.; Fu, H.; Cao, Y.; Fang, G.; Liu, B.; Wu, J.; et al. Andrade-Oliveira Salvianolic Acid B Modulates Caspase-1—Mediated Pyroptosis in Renal Ischemia-Reperfusion Injury via Nrf2 Pathway. Front. Pharmacol. 2020, 11, 541426. [Google Scholar] [CrossRef]
  99. Xiao, C.; Zhao, H.; Zhu, H.; Zhang, Y.; Su, Q.; Zhao, F.; Wang, R. Tisp40 Induces Tubular Epithelial Cell GSDMD-Mediated Pyroptosis in Renal Ischemia-Reperfusion Injury via NF-κB Signaling. Front. Physiol. 2020, 11, 906. [Google Scholar] [CrossRef]
  100. Wu, W.; Liu, D.; Zhao, Y.; Zhang, T.; Ma, J.; Wang, D.; Li, J.; Qian, W.; Zhang, Z.; Yu, D.; et al. Cholecalciferol pretreatment ameliorates ischemia/reperfusion-induced acute kidney injury through inhibiting ROS production, NF-κB pathway and pyroptosis. Acta Histochem. 2022, 124, 151875. [Google Scholar] [CrossRef]
  101. Wang, R.; Zhao, H.; Zhang, Y.; Zhu, H.; Su, Q.; Qi, H.; Deng, J.; Xiao, C. Identification of MicroRNA-92a-3p as an Essential Regulator of Tubular Epithelial Cell Pyroptosis by Targeting Nrf1 via HO-1. Front. Genet. 2021, 11, 616947. [Google Scholar] [CrossRef] [PubMed]
  102. Fan, Y.; Ma, M.; Feng, X.; Song, T.; Wei, Q.; Lin, T. Overexpression of aquaporin 2 in renal tubular epithelial cells alleviates pyroptosis. Transl. Androl. Urol. 2021, 10, 2340–2350. [Google Scholar] [CrossRef] [PubMed]
  103. Tonnus, W.; Maremonti, F.; Belavgeni, A.; Latk, M.; Kusunoki, Y.; Brucker, A.; von Massenhausen, A.; Meyer, C.; Locke, S.; Gembardt, F.; et al. Gasdermin D-deficient mice are hypersensitive to acute kidney injury. Cell Death Dis. 2022, 13, 792. [Google Scholar] [CrossRef] [PubMed]
  104. Li, Z.; Zhao, F.; Cao, Y.; Zhang, J.; Shi, P.; Sun, X.; Zhang, F.; Tong, L. DHA attenuates hepatic ischemia reperfusion injury by inhibiting pyroptosis and activating PI3K/Akt pathway. Eur. J. Pharmacol. 2018, 835, 1–10. [Google Scholar] [CrossRef] [PubMed]
  105. Pan, Y.; Yu, S.; Wang, J.; Li, W.; Li, H.; Bai, C.; Sheng, Y.; Li, M.; Wang, C.; Liu, J.; et al. N-acetyl-L-tryptophan attenuates hepatic ischemia-reperfusion injury via regulating TLR4/NLRP3 signaling pathway in rats. PeerJ 2021, 9, e11909. [Google Scholar] [CrossRef]
  106. Fagenson, A.M.; Xu, K.; Saaoud, F.; Nanayakkara, G.; Jhala, N.C.; Liu, L.; Drummer, C.; Sun, Y.; Lau, K.N.; Di Carlo, A.; et al. Liver Ischemia Reperfusion Injury, Enhanced by Trained Immunity, Is Attenuated in Caspase 1/Caspase 11 Double Gene Knockout Mice. Pathogens 2020, 9, 879. [Google Scholar] [CrossRef]
  107. Hua, S.; Ma, M.; Fei, X.; Zhang, Y.; Gong, F.; Fang, M. Glycyrrhizin attenuates hepatic ischemia-reperfusion injury by suppressing HMGB1-dependent GSDMD-mediated kupffer cells pyroptosis. Int. Immunopharmacol. 2019, 68, 145–155. [Google Scholar] [CrossRef]
  108. Wang, X.; Zheng, W.; Bai, Y.; Li, Y.; Xin, Y.; Wang, J.; Chang, Y.; Zhang, L. Carbon Monoxide–Releasing Molecule-3 Alleviates Kupffer Cell Pyroptosis Induced by Hemorrhagic Shock and Resuscitation via sGC-cGMP Signal Pathway. Inflammation 2021, 44, 1330–1344. [Google Scholar] [CrossRef]
  109. Kolachala, V.L.; Lopez, C.; Shen, M.; Shayakhmetov, D.; Gupta, N.A. Ischemia reperfusion injury induces pyroptosis and mediates injury in steatotic liver thorough Caspase 1 activation. Apoptosis 2021, 26, 361–370. [Google Scholar] [CrossRef]
  110. Wu, X.; Chen, Y.; Liu, C.; Gong, J.; Xu, X. STING Induces Liver Ischemia-Reperfusion Injury by Promoting Calcium-Dependent Caspase 1-GSDMD Processing in Macrophages. Oxidative Med. Cell. Longev. 2022, 2022, 8123157. [Google Scholar] [CrossRef]
  111. El-Sisi, A.E.E.; Sokar, S.S.; Shebl, A.M.; Mohamed, D.Z.; Abu-Risha, S.E. Octreotide and melatonin alleviate inflammasome-induced pyroptosis through inhibition of TLR4-NF-κB-NLRP3 pathway in hepatic ischemia/reperfusion injury. Toxicol. Appl. Pharmacol. 2021, 410, 115340. [Google Scholar] [CrossRef] [PubMed]
  112. Jia, Y.; Cui, R.; Wang, C.; Feng, Y.; Li, Z.; Tong, Y.; Qu, K.; Liu, C.; Zhang, J. Metformin protects against intestinal ischemia-reperfusion injury and cell pyroptosis via TXNIP-NLRP3-GSDMD pathway. Redox Biol. 2020, 32, 101534. [Google Scholar] [CrossRef] [PubMed]
  113. Wan, P.; Su, W.; Zhang, Y.; Li, Z.; Deng, C.; Li, J.; Jiang, N.; Huang, S.; Long, E.; Zhuo, Y. LncRNA H19 initiates microglial pyroptosis and neuronal death in retinal ischemia/reperfusion injury. Cell Death Differ. 2020, 27, 176–191. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  114. Zhou, P.; Guo, H.; Li, Y.; Liu, Q.; Qiao, X.; Lu, Y.; Mei, P.; Zheng, Z.; Li, J. Monocytes promote pyroptosis of endothelial cells during lung ischemia-reperfusion via IL-1R/NF-κB/NLRP3 signaling. Life Sci. 2021, 276, 119402. [Google Scholar] [CrossRef] [PubMed]
  115. Zhou, P.; Song, N.C.; Zheng, Z.K.; Li, Y.Q.; Li, J.S. MMP2 and MMP9 contribute to lung ischemia-reperfusion injury via promoting pyroptosis in mice. BMC Pulm. Med. 2022, 22, 230. [Google Scholar] [CrossRef]
  116. Wu, X.; Li, Y.; Zhang, S.; Zhou, X. Ferroptosis as a novel therapeutic target for cardiovascular disease. Theranostics 2021, 11, 3052–3059. [Google Scholar] [CrossRef] [PubMed]
  117. Muller, T.; Dewitz, C.; Schmitz, J.; Schroder, A.S.; Brasen, J.H.; Stockwell, B.R.; Murphy, J.M.; Kunzendorf, U.; Krautwald, S. Necroptosis and ferroptosis are alternative cell death pathways that operate in acute kidney failure. Cell. Mol. Life Sci. 2017, 74, 3631–3645. [Google Scholar] [CrossRef] [Green Version]
  118. Yu, Y.; Liu, S.; Zhou, Y.; Huang, K.; Wu, B.; Lin, Z.; Zhu, C.; Xue, Y.; Ji, K. Shexiang Baoxin Pill attenuates myocardial ischemia/reperfusion injury by activating autophagy via modulating the ceRNA-Map3k8 pathway. Phytomedicine 2022, 104, 154336. [Google Scholar] [CrossRef]
  119. Malireddi, R.; Gurung, P.; Kesavardhana, S.; Samir, P.; Burton, A.; Mummareddy, H.; Vogel, P.; Pelletier, S.; Burgula, S.; Kanneganti, T.D. Innate immune priming in the absence of TAK1 drives RIPK1 kinase activity-independent pyroptosis, apoptosis, necroptosis, and inflammatory disease. J. Exp. Med. 2020, 217, e20191644. [Google Scholar] [CrossRef]
  120. Malireddi, R.; Kesavardhana, S.; Kanneganti, T.D. ZBP1 and TAK1: Master Regulators of NLRP3 Inflammasome/Pyroptosis, Apoptosis, and Necroptosis (PAN-optosis). Front. Cell. Infect. Microbiol. 2019, 9, 406. [Google Scholar] [CrossRef]
  121. Yan, W.T.; Zhao, W.J.; Hu, X.M.; Ban, X.X.; Ning, W.Y.; Wan, H.; Zhang, Q.; Xiong, K. PANoptosis-like cell death in ischemia/reperfusion injury of retinal neurons. Neural Regen. Res. 2023, 18, 357–363. [Google Scholar]
  122. Yan, W.T.; Yang, Y.D.; Hu, X.M.; Ning, W.Y.; Liao, L.S.; Lu, S.; Zhao, W.J.; Zhang, Q.; Xiong, K. Do pyroptosis, apoptosis, and necroptosis (PANoptosis) exist in cerebral ischemia? Evidence from cell and rodent studies. Neural Regen. Res. 2022, 17, 1761–1768. [Google Scholar]
  123. Zhang, Z.; Zhang, Z.; Chen, M.; Yang, Y.; Li, R.; Xu, J.; Yang, C.; Li, Y.; Chen, H.; Liu, S.; et al. Inhibition of GSDMD Activates Poly(ADP-ribosyl)ation and Promotes Myocardial Ischemia-Reperfusion Injury. Oxidative Med. Cell. Longev. 2022, 2022, 1115749. [Google Scholar] [CrossRef]
Biomolecules 12 01625 g001 550
Figure 1. An overview of the mechanisms of pyroptosis. In the canonical pathway, PAMPs and DAMPs receive signaling molecule stimulation and assemble with pro-caspase-1 and ASC to form inflammasomes and active caspase-1. Activated caspase-1 cleaves GSDMD into GSDMD-N and GDSMD-C and lyses the precursors of IL-1β and IL-18 (pro-ILβ and pro-IL-18, respectively). GSDMD-N perforates the cell membrane by forming non-selective pores, further causing water influx and cell swelling and bursting. In addition, IL-1β and IL-18 are secreted from the pores formed by GSDMD-N. In the noncanonical pathway, LPS activates caspase-4/5 and caspase-11, triggering pyroptosis by cleaving GSDMD. In addition, the cleavage of GSDMD results in efflux of K+, ultimately giving rise to the assembly of an NLRP3 inflammasome. In the caspase-3-mediated pathway, active caspase-3 cleaves GSDME to form GSDME-N, inducing cell pyroptosis. In the caspase-8-mediated pathway, inhibiting TAK1 induces the activation of caspase-8, which cleaves GSDMD or GSDME and results in pyroptosis.
Figure 1. An overview of the mechanisms of pyroptosis. In the canonical pathway, PAMPs and DAMPs receive signaling molecule stimulation and assemble with pro-caspase-1 and ASC to form inflammasomes and active caspase-1. Activated caspase-1 cleaves GSDMD into GSDMD-N and GDSMD-C and lyses the precursors of IL-1β and IL-18 (pro-ILβ and pro-IL-18, respectively). GSDMD-N perforates the cell membrane by forming non-selective pores, further causing water influx and cell swelling and bursting. In addition, IL-1β and IL-18 are secreted from the pores formed by GSDMD-N. In the noncanonical pathway, LPS activates caspase-4/5 and caspase-11, triggering pyroptosis by cleaving GSDMD. In addition, the cleavage of GSDMD results in efflux of K+, ultimately giving rise to the assembly of an NLRP3 inflammasome. In the caspase-3-mediated pathway, active caspase-3 cleaves GSDME to form GSDME-N, inducing cell pyroptosis. In the caspase-8-mediated pathway, inhibiting TAK1 induces the activation of caspase-8, which cleaves GSDMD or GSDME and results in pyroptosis.
Biomolecules 12 01625 g001
Biomolecules 12 01625 g002 550
Figure 2. Schematic diagram demonstrating the link between pyroptosis and I/R injury. Following I/R insults, NF-κB signaling (priming) is activated by Toll-like receptors (TLRs), and ROS are also produced, resulting in NLRP3 inflammasome assembly and caspase-1 activation. Activated caspase-1 cleaves GSDMD into GSDMD-N and GDSMD-C and lyses the precursors of IL-1β and IL-18 (pro-ILβ and pro-IL-18, respectively) to form mature IL-1β and IL-18. Then, GSDMD-N oligomerizes and penetrates the cell membrane, forming non-selective pores on the membrane to release IL-1β and IL-18.
Figure 2. Schematic diagram demonstrating the link between pyroptosis and I/R injury. Following I/R insults, NF-κB signaling (priming) is activated by Toll-like receptors (TLRs), and ROS are also produced, resulting in NLRP3 inflammasome assembly and caspase-1 activation. Activated caspase-1 cleaves GSDMD into GSDMD-N and GDSMD-C and lyses the precursors of IL-1β and IL-18 (pro-ILβ and pro-IL-18, respectively) to form mature IL-1β and IL-18. Then, GSDMD-N oligomerizes and penetrates the cell membrane, forming non-selective pores on the membrane to release IL-1β and IL-18.
Biomolecules 12 01625 g002
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Zheng, Y.; Xu, X.; Chi, F.; Cong, N. Pyroptosis: A Newly Discovered Therapeutic Target for Ischemia-Reperfusion Injury. Biomolecules 2022, 12, 1625. https://doi.org/10.3390/biom12111625

AMA Style

Zheng Y, Xu X, Chi F, Cong N. Pyroptosis: A Newly Discovered Therapeutic Target for Ischemia-Reperfusion Injury. Biomolecules. 2022; 12(11):1625. https://doi.org/10.3390/biom12111625

Chicago/Turabian Style

Zheng, Yu, Xinda Xu, Fanglu Chi, and Ning Cong. 2022. "Pyroptosis: A Newly Discovered Therapeutic Target for Ischemia-Reperfusion Injury" Biomolecules 12, no. 11: 1625. https://doi.org/10.3390/biom12111625

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop