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Open accessJournal ArticleDOI: 10.1038/S41418-021-00755-6

GSDME-mediated pyroptosis promotes inflammation and fibrosis in obstructive nephropathy.

04 Mar 2021-Cell Death & Differentiation (Nature Publishing Group)-Vol. 28, Iss: 8, pp 2333-2350
Abstract: Renal tubular cell (RTC) death and inflammation contribute to the progression of obstructive nephropathy, but its underlying mechanisms have not been fully elucidated. Here, we showed that Gasdermin E (GSDME) expression level and GSDME-N domain generation determined the RTC fate response to TNFα under the condition of oxygen-glucose-serum deprivation. Deletion of Caspase-3 (Casp3) or Gsdme alleviated renal tubule damage and inflammation and finally prevented the development of hydronephrosis and kidney fibrosis after ureteral obstruction. Using bone marrow transplantation and cell type-specific Casp3 knockout mice, we demonstrated that Casp3/GSDME-mediated pyroptosis in renal parenchymal cells, but not in hematopoietic cells, played predominant roles in this process. We further showed that HMGB1 released from pyroptotic RTCs amplified inflammatory responses, which critically contributed to renal fibrogenesis. Specific deletion of Hmgb1 in RTCs alleviated caspase11 and IL-1β activation in macrophages. Collectively, our results uncovered that TNFα/Casp3/GSDME-mediated pyroptosis is responsible for the initiation of ureteral obstruction-induced renal tubule injury, which subsequentially contributes to the late-stage progression of hydronephrosis, inflammation, and fibrosis. This novel mechanism will provide valuable therapeutic insights for the treatment of obstructive nephropathy.

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Topics: Pyroptosis (60%), Obstructive Nephropathy (56%), Fibrosis (53%) ... show more
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7 results found


Open accessJournal ArticleDOI: 10.1155/2021/6686617
Ke-jia Zhang1, Qi Wu1, Shi-min Jiang1, Lei Ding1  +5 moreInstitutions (1)
Abstract: Pyroptosis is a pattern of programmed cell death that significantly differs from apoptosis and autophagy in terms of cell morphology and function. The process of pyroptosis is characterized predominantly by the formation of gasdermin protein family-mediated membrane perforation, cell collapse, and the release of inflammatory factors, including IL-1β and IL-18. In recent years, with the rise of pyroptosis research, scholars have devoted time to study the mechanism of pyroptosis in kidney-related diseases. Pyroptosis is probably involved in kidney diseases through two pathways: the caspase-1-mediated canonical pathway and the caspase-4/5/11-mediated noncanonical pathway. In addition, some scholars have identified targets for the treatment of kidney-related diseases from the viewpoint of pyroptosis and developed corresponding medicines, which may become a recommendation for prognosis, targeted treatment, and clinical diagnosis of kidney diseases. This paper focuses on the up-to-date advances in the field of pyroptosis, especially on the key pathogenic role of pyroptosis in the development and progression of kidney diseases. It presents a more in-depth understanding of the pathogenesis of kidney diseases and introduces novel therapeutic targets for the prevention and clinical treatment of kidney diseases.

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Topics: Pyroptosis (68%), Cell morphology (53%)

3 Citations


Journal ArticleDOI: 10.1016/J.JMB.2021.167253
Emilie Bourdonnay1, Thomas Henry1Institutions (1)
Abstract: Gasdermins (GSDM) are a family of six homologous proteins (GSDMA to E and Pejvakin) in humans. GSDMA-E are pore-forming proteins targeting the plasma membrane to trigger a rapid cell death termed pyroptosis or bacterial membranes to promote antibacterial immune defenses. Activation of GSDM relies on a proteolytic cleavage but is highly dependent on GSDM expression levels. The different GSDM genes have tissue-specific expression pattern although metabolic, environmental signals, cell stress and numerous cytokines modulate their expression levels in tissues. Furthermore, expression of GSDM genes can be modulated by polymorphisms and have been associated with susceptibility to asthma, inflammatory bowel diseases and rhinovirus wheezing illness. Finally, the expression level of GSDMs controls the balance between apoptosis and pyroptosis affecting both the response and the toxicity to chemotactic drugs and antitumoral treatments. Numerous cancer demonstrate positive or negative modulation of GSDM expression levels correlating with distinct tumor-specific prognosis. In this review, we present the transcriptional and epigenetic mechanisms controlling GSDM levels and their functional consequences in asthma, infection, cancers and inflammatory bowel disease to highlight how this first layer of regulations has key consequences on disease susceptibility and response to treatment.

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Topics: Pyroptosis (55%)

Open accessJournal ArticleDOI: 10.2147/CMAR.S318980
Xiao Xie1, Fangbao Ding1, Haibo Xiao1Institutions (1)
Abstract: Background Non-small cell lung cancer (NSCLC) is a subtype of lung cancer which seriously threatens the health of people. Circular RNAs (CircRNAs) are endogenous RNAs which have stable closed structure; they are known to be involved in tumorigenesis of NSCLC. Meanwhile, hsa_circ_0000729 was reported to be upregulated in NSCLC. Nevertheless, the function of hsa_circ_0000729 in NSCLC remains unclear. Methods Western blot and RT-qPCR were performed to investigate protein and mRNA levels, respectively. CCK-8 assay was performed to test the cell viability and cell death was investigated by flow cytometry. NSCLC cell pyroptosis was observed by electron microscope. In addition, the migration and invasion of NSCLC cells were detected by wound healing and transwell assay. The relation among hsa_circ_0000729, miR-1281 and FOXO3 was explored by dual luciferase reporter assay and RNA pull-down. Results Hsa_circ_0000729 was found to be upregulated in NSCLC cells, and hsa_circ_0000729 knockdown obviously suppressed the proliferation of NSCLC cells through inducing pyroptosis. In addition, silencing of hsa_circ_0000729 notably inhibited the invasion and migration of NSCLC cells. Meanwhile, hsa_circ_0000729 could bind with miR-1281, and FOXO3 was directly targeted by miR-1281. Moreover, the anti-tumor effect of hsa_circ_0000729 siRNAs on NSCLC was markedly reversed by miR-1281 antagomir. Furthermore, silencing of hsa_circ_0000729 inhibited the tumor growth of NSCLC in vivo. Conclusion Knockdown of hsa_circ_0000729 inhibits the tumorigenesis of NSCLC through mediation of miR-1281/FOXO3 axis. Thus, hsa_circ_0000729 might be served as a crucial mediator in NSCLC.

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Open accessJournal ArticleDOI: 10.3389/FCELL.2021.754134
Mengying Wu1, Weiwei Xia1, Qianqian Jin1, Anning Zhou1  +7 moreInstitutions (1)
Abstract: Renal fibrosis contributes to kidney dysfunction in various chronic kidney diseases (CKDs). Renal fibrosis can be driven by renal tubular cell death and inflammation. Deletion of gasdermin E (GSDME), an executor of pyroptosis, has been reported to suppress renal tubular cell pyroptosis in several models of kidney injury. However, additional evidence confirming the role of GSDME in regulating renal fibrosis and kidney function in different CKDs is required. In our study, N-GSDME expression was significantly elevated in CKD models in vivo and in vitro. GSDME deletion alleviated renal fibrosis and inflammation in both unilateral ureteral ligation (UUO) and 5/6 nephrectomy (5/6Nx) models along with the attenuation of renal dysfunction. N-GSDME overexpression had a detrimental effect on fibrotic responses in UUO kidneys and TGF-β1-treated renal tubular epithelial cells. In addition, administration of caspase-3 inhibitor Z-DEVD-FMK, which inhibits caspase-3-mediated GSDME cleavage, protected against renal fibrosis both in vivo and in vitro. Collectively, these results provide evidence that the activation of GSDME is critical in regulating both renal fibrosis and kidney dysfunction possibly via promoting inflammatory responses in CKD. These findings may offer new insights into the identification of new therapeutic targets for protecting against CKDs.

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Topics: Renal fibrosis (72%), Nephrectomy (57%), Renal function (53%) ... show more

Open accessJournal ArticleDOI: 10.3389/FPHAR.2021.780790
Abstract: Pyroptosis, a newly identified type of lytic programmed cell death (PCD), is featured in pore formation in the plasma membrane, swelling, and cell rupture with secretion of cellular contents, especially the inflammatory cytokines. A large number of studies have shown that pyroptosis includes not only the GSDMD involved caspase-1-dependent classical pathway and caspase-11/4/5-dependent non-classical pathway, but also the GSDME involved caspase-3 (Casp3) dependent pathway. Diabetic nephropathy (DN) is one of the most serious microvascular complications in diabetes. Present evidence suggestes that pyroptosis promotes the progression of several diabetic complications including DN. The underlying mechanism mediating renoprotection conferred by GSDME regulation in the diabetic kidney, specifically in human tubular cells has been investigated. Z-DEVD-FMK, the inhibitor of Casp3, ameliorated albuminuria, renal function, and tubulointerstitial fibrosis in diabetic mice. The nephroprotection mediated by Z-DEVDFMK was potentially associated with inhibition of GSDME. In vitro, molecular and morphological features of secondary necrosis were observed in glucose-stimulated HK-2 cells, evidenced by active GSDME cleavage, ballooning of the cell membrane, and release of cellular contents. Based on this, it is not difficult to conclude that therapies targeting Casp3/GSDME dependent pyroptosis show great application prospects in DN, and novel nephroprotective strategy using GSDME-derived peptides directed against Casp3-induced cell death in vitro and in vivo may be a key breakthrough for this goal. Therefore, in the mini-review, we introduced the history of pyroptosis; gasdermin family proteins especially GSDME, and GSDME mediated pyroptosis in DN, expecting this novel mechanism may provide valuable therapeutic insights for the treatment of DN.

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Topics: Pyroptosis (68%)

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47 results found


Journal ArticleDOI: 10.1038/NATURE15514
Jianjin Shi1, Yue Zhao, Kun Wang, Xuyan Shi  +6 moreInstitutions (2)
29 Oct 2015-Nature
Abstract: Inflammatory caspases (caspase-1, -4, -5 and -11) are critical for innate defences. Caspase-1 is activated by ligands of various canonical inflammasomes, and caspase-4, -5 and -11 directly recognize bacterial lipopolysaccharide, both of which trigger pyroptosis. Despite the crucial role in immunity and endotoxic shock, the mechanism for pyroptosis induction by inflammatory caspases is unknown. Here we identify gasdermin D (Gsdmd) by genome-wide clustered regularly interspaced palindromic repeat (CRISPR)-Cas9 nuclease screens of caspase-11- and caspase-1-mediated pyroptosis in mouse bone marrow macrophages. GSDMD-deficient cells resisted the induction of pyroptosis by cytosolic lipopolysaccharide and known canonical inflammasome ligands. Interleukin-1β release was also diminished in Gsdmd(-/-) cells, despite intact processing by caspase-1. Caspase-1 and caspase-4/5/11 specifically cleaved the linker between the amino-terminal gasdermin-N and carboxy-terminal gasdermin-C domains in GSDMD, which was required and sufficient for pyroptosis. The cleavage released the intramolecular inhibition on the gasdermin-N domain that showed intrinsic pyroptosis-inducing activity. Other gasdermin family members were not cleaved by inflammatory caspases but shared the autoinhibition; gain-of-function mutations in Gsdma3 that cause alopecia and skin defects disrupted the autoinhibition, allowing its gasdermin-N domain to trigger pyroptosis. These findings offer insight into inflammasome-mediated immunity/diseases and also change our understanding of pyroptosis and programmed necrosis.

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Topics: Pyroptosis (70%), Caspase-11 (70%), Caspase 1 (68%) ... show more

2,023 Citations


Journal ArticleDOI: 10.1038/NATURE18590
Jingjin Ding1, Kun Wang, Wang Liu, Yang She1  +6 moreInstitutions (2)
07 Jul 2016-Nature
Abstract: The N-terminal domains of gasdermin proteins cause pyroptotic cell death by oligomerizing to form membrane pores.

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898 Citations


Open accessJournal ArticleDOI: 10.1038/CR.2015.139
Wan-ting He1, Haoqiang Wan1, Lichen Hu1, Pengda Chen1  +5 moreInstitutions (1)
27 Nov 2015-Cell Research
Abstract: Inflammasome is an intracellular signaling complex of the innate immune system. Activation of inflammasomes promotes the secretion of interleukin 1β (IL-1β) and IL-18 and triggers pyroptosis. Caspase-1 and -11 (or -4/5 in human) in the canonical and non-canonical inflammasome pathways, respectively, are crucial for inflammasome-mediated inflammatory responses. Here we report that gasdermin D (GSDMD) is another crucial component of inflammasomes. We discovered the presence of GSDMD protein in nigericin-induced NLRP3 inflammasomes by a quantitative mass spectrometry-based analysis. Gene deletion of GSDMD demonstrated that GSDMD is required for pyroptosis and for the secretion but not proteolytic maturation of IL-1β in both canonical and non-canonical inflammasome responses. It was known that GSDMD is a substrate of caspase-1 and we showed its cleavage at the predicted site during inflammasome activation and that this cleavage was required for pyroptosis and IL-1β secretion. Expression of the N-terminal proteolytic fragment of GSDMD can trigger cell death and N-terminal modification such as tagging with Flag sequence disrupted the function of GSDMD. We also found that pro-caspase-1 is capable of processing GSDMD and ASC is not essential for GSDMD to function. Further analyses of LPS plus nigericin- or Salmonella typhimurium-treated macrophage cell lines and primary cells showed that apoptosis became apparent in Gsdmd(-/-) cells, indicating a suppression of apoptosis by pyroptosis. The induction of apoptosis required NLRP3 or other inflammasome receptors and ASC, and caspase-1 may partially contribute to the activation of apoptotic caspases in Gsdmd(-/-) cells. These data provide new insights into the molecular mechanisms of pyroptosis and reveal an unexpected interplay between apoptosis and pyroptosis.

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Topics: Caspase-11 (72%), Pyroptosis (70%), Inflammasome (66%) ... show more

836 Citations


Open accessJournal ArticleDOI: 10.1038/KI.2009.86
Abstract: Renal fibrosis is the hallmark of progressive renal disease of virtually any etiology. The model of unilateral ureteral obstruction (UUO) in the rodent generates progressive renal fibrosis. Surgically created UUO can be experimentally manipulated with respect to timing, severity, and duration, while reversal of the obstruction permits the study of recovery. The use of genetically engineered mice has greatly expanded the utility of the model in studying molecular mechanisms underlying the renal response to UUO. Ureteral obstruction results in marked renal hemodynamic and metabolic changes, followed by tubular injury and cell death by apoptosis or necrosis, with interstitial macrophage infiltration. Proliferation of interstitial fibroblasts with myofibroblast transformation leads to excess deposition of the extracellular matrix and renal fibrosis. Phenotypic transition of resident renal tubular cells, endothelial cells, and pericytes has also been implicated in this process. Technical aspects of the UUO model are discussed in this review, including the importance of rodent species or strain, the age of the animal, surgical procedures, and histological methods. The UUO model is likely to reveal useful biomarkers of progression of renal disease, as well as new therapies, which are desperately needed to allow intervention before the establishment of irreversible renal injury.

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Topics: Renal fibrosis (67%), Fibrosis (54%), Nephrology (54%) ... show more

688 Citations


Journal ArticleDOI: 10.1038/NATURE22393
Yupeng Wang1, Wenqing Gao1, Xuyan Shi1, Jingjin Ding  +4 moreInstitutions (1)
01 May 2017-Nature
Abstract: Pyroptosis is a form of cell death that is critical for immunity. It can be induced by the canonical caspase-1 inflammasomes or by activation of caspase-4, -5 and -11 by cytosolic lipopolysaccharide. The caspases cleave gasdermin D (GSDMD) in its middle linker to release autoinhibition on its gasdermin-N domain, which executes pyroptosis via its pore-forming activity. GSDMD belongs to a gasdermin family that shares the pore-forming domain. The functions and mechanisms of activation of other gasdermins are unknown. Here we show that GSDME, which was originally identified as DFNA5 (deafness, autosomal dominant 5), can switch caspase-3-mediated apoptosis induced by TNF or chemotherapy drugs to pyroptosis. GSDME was specifically cleaved by caspase-3 in its linker, generating a GSDME-N fragment that perforates membranes and thereby induces pyroptosis. After chemotherapy, cleavage of GSDME by caspase-3 induced pyroptosis in certain GSDME-expressing cancer cells. GSDME was silenced in most cancer cells but expressed in many normal tissues. Human primary cells exhibited GSDME-dependent pyroptosis upon activation of caspase-3 by chemotherapy drugs. Gsdme-/- (also known as Dfna5-/-) mice were protected from chemotherapy-induced tissue damage and weight loss. These findings suggest that caspase-3 activation can trigger necrosis by cleaving GSDME and offer new insights into cancer chemotherapy.

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Topics: Pyroptosis (69%), Caspase 1 (68%), Caspase (51%)

660 Citations


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