GSDME-mediated pyroptosis promotes inflammation and fibrosis in obstructive nephropathy.
TL;DR: In this paper, the authors showed 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.
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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TL;DR: In this paper , the potential therapies targeted to these signaling pathways are also introduced and the key signaling pathways of lipotoxicity, oxidative stress, inflammation, and myofibroblasts activation in kidneys with chronic injury, and the targeted drugs based on the latest studies.
Abstract: Abstract Chronic kidney disease (CKD) is a chronic renal dysfunction syndrome that is characterized by nephron loss, inflammation, myofibroblasts activation, and extracellular matrix (ECM) deposition. Lipotoxicity and oxidative stress are the driving force for the loss of nephron including tubules, glomerulus, and endothelium. NLRP3 inflammasome signaling, MAPK signaling, PI3K/Akt signaling, and RAAS signaling involves in lipotoxicity. The upregulated Nox expression and the decreased Nrf2 expression result in oxidative stress directly. The injured renal resident cells release proinflammatory cytokines and chemokines to recruit immune cells such as macrophages from bone marrow. NF-κB signaling, NLRP3 inflammasome signaling, JAK-STAT signaling, Toll-like receptor signaling, and cGAS-STING signaling are major signaling pathways that mediate inflammation in inflammatory cells including immune cells and injured renal resident cells. The inflammatory cells produce and secret a great number of profibrotic cytokines such as TGF-β1, Wnt ligands, and angiotensin II. TGF-β signaling, Wnt signaling, RAAS signaling, and Notch signaling evoke the activation of myofibroblasts and promote the generation of ECM. The potential therapies targeted to these signaling pathways are also introduced here. In this review, we update the key signaling pathways of lipotoxicity, oxidative stress, inflammation, and myofibroblasts activation in kidneys with chronic injury, and the targeted drugs based on the latest studies. Unifying these pathways and the targeted therapies will be instrumental to advance further basic and clinical investigation in CKD.
34 citations
TL;DR: In this paper, the up-to-date advances in the field of pyroptosis, especially on the key pathogenic role of pyroposis in the development and progression of kidney diseases, are discussed.
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.
23 citations
TL;DR: The findings revealed that ATF3 has the potential to be used as a promising therapeutic target against IDD, and positively regulated tert-butyl hydroperoxide-induced nucleus pulposus cell (NPC) FAoptosis, ROS production, inflammatory response, and extracellular matrix (ECM) degradation.
Abstract: Intervertebral disc degeneration (IDD), being the predominant root cause of lower back pain, has led to an enormous socioeconomic burden in the world. Ferroptosis is an iron-dependent nonapoptotic and nonpyroptotic programmed cell death associated with an increase in reactive oxygen species (ROS), which has been implicated in the pathogenesis of IDD. Activation transcription factor 3 (ATF3) is widely reported to promote ferroptosis and apoptosis in multiple diseases, but its roles and underlying regulatory mechanism in IDD have not been identified. FAoptosis is defined as a mixed cell death consisting of ferroptosis and apoptosis. The loss- and gain-of-function experiments demonstrated that ATF3 positively regulated tert-butyl hydroperoxide- (TBHP-) induced nucleus pulposus cell (NPC) FAoptosis, ROS production, inflammatory response, and extracellular matrix (ECM) degradation. Furthermore, silencing ATF3 ameliorated the progression of IDD in vivo, whereas its overexpression showed the opposite phenotype. Bioinformatics analysis and molecular experiments corroborated that ATF3 is a direct target of miR-874-3p, suggesting that the upregulation of ATF3 in IDD might be caused at least in part due to the downregulation of miR-874-3p in IDD, thereby relieving the inhibition of ATF3 by miR-874-3p. The findings revealed that ATF3 has the potential to be used as a promising therapeutic target against IDD.
12 citations
TL;DR: In this article, the authors introduced pyroptosis, a newly identified type of lytic programmed cell death, is featured in pore formation in the plasma membrane, swelling, and cell rupture with secretion of cellular contents, especially the inflammatory cytokines.
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.
11 citations
TL;DR: A review of the recent advances in pathological mechanisms of pyroptosis in kidney disease and highlight the potential therapeutic strategies in future can be found in this paper, where the authors also discuss the potential treatment strategies in the future.
11 citations
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TL;DR: Gasdermin D (Gsdmd) is identified by genome-wide clustered regularly interspaced palindromic repeat-Cas9 nuclease screens of caspase-11- and caspasing-1-mediated pyroptosis in mouse bone marrow macrophages to offer insight into inflammasome-mediated immunity/diseases and change the understanding of pyroPTosis and programmed necrosis.
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.
3,554 citations
TL;DR: It is demonstrated that the liposome-leakage and pore-forming activities of the gasdermin-N domain are required for pyroptosis and provide insights into the roles of theGasdermin family in necrosis, immunity and diseases.
Abstract: The N-terminal domains of gasdermin proteins cause pyroptotic cell death by oligomerizing to form membrane pores.
1,567 citations
TL;DR: It is shown 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, suggesting that casp enzyme activation can trigger necrosis by cleaving G SDME and offer new insights into cancer chemotherapy.
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.
1,458 citations
TL;DR: It is reported that gasdermin D (GSDMD) is another crucial component of inflammasomes and the presence of GSDMD protein in nigericin-induced NLRP3 inflammaomes is discovered by a quantitative mass spectrometry-based analysis.
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.
1,440 citations
TL;DR: 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.
824 citations