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Nature Reviews. Drug Discovery May 2021Gasdermins were recently identified as the mediators of pyroptosis - inflammatory cell death triggered by cytosolic sensing of invasive infection and danger signals.... (Review)
Review
Gasdermins were recently identified as the mediators of pyroptosis - inflammatory cell death triggered by cytosolic sensing of invasive infection and danger signals. Upon activation, gasdermins form cell membrane pores, which release pro-inflammatory cytokines and alarmins and damage the integrity of the cell membrane. Roles for gasdermins in autoimmune and inflammatory diseases, infectious diseases, deafness and cancer are emerging, revealing potential novel therapeutic avenues. Here, we review current knowledge of the family of gasdermins, focusing on their mechanisms of action and roles in normal physiology and disease. Efforts to develop drugs to modulate gasdermin activity to reduce inflammation or activate more potent immune responses are highlighted.
Topics: Animals; Anti-Inflammatory Agents; Cytokines; Humans; Immunity; Inflammation Mediators; Neoplasm Proteins; Pyroptosis
PubMed: 33692549
DOI: 10.1038/s41573-021-00154-z -
Annual Review of Pathology Jan 2022The involvement of inflammasomes in the proinflammatory response observed in chronic liver diseases, such as alcohol-associated liver disease (ALD) and nonalcoholic... (Review)
Review
The involvement of inflammasomes in the proinflammatory response observed in chronic liver diseases, such as alcohol-associated liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD), is widely recognized. Although there are different types of inflammasomes, most studies to date have given attention to NLRP3 (nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3) in the pathogenesis of ALD, NAFLD/nonalcoholic steatohepatitis, and fibrosis. Canonical inflammasomes are intracellular multiprotein complexes that are assembled after the sensing of danger signals and activate caspase-1, which matures interleukin (IL)-1β, IL-18, and IL-37 and also induces a form of cell death called pyroptosis. Noncanonical inflammasomes activate caspase-11 to induce pyroptosis. We discuss the different types of inflammasomes involved in liver diseases with a focus on () signals and mechanisms of inflammasome activation, () the role of different types of inflammasomes and their products in the pathogenesis of liver diseases, and () potential therapeutic strategies targeting components of the inflammasomes or cytokines produced upon inflammasome activation.
Topics: Humans; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Non-alcoholic Fatty Liver Disease; Pyroptosis
PubMed: 34752711
DOI: 10.1146/annurev-pathmechdis-032521-102529 -
Frontiers in Immunology 2021Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Recently was been found that pyroptosis is a unique form of... (Review)
Review
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Recently was been found that pyroptosis is a unique form of proinflammatory programmed death, that is different from apoptosis. A growing number of studies have investigated pyroptosis and its relationship with sepsis, including the mechanisms, role, and relevant targets of pyroptosis in sepsis. While moderate pyroptosis in sepsis can control pathogen infection, excessive pyroptosis can lead to a dysregulated host immune response and even organ dysfunction. This review provides an overview of the mechanisms and potential therapeutic targets underlying pyroptosis in sepsis identified in recent decades, looking forward to the future direction of treatment for sepsis.
Topics: Alarmins; Apoptosis; Caspases; Cytokines; Disseminated Intravascular Coagulation; Drugs, Chinese Herbal; Heart; Humans; Lung; Pyroptosis; Sepsis
PubMed: 34305952
DOI: 10.3389/fimmu.2021.711939 -
Journal of Experimental & Clinical... Aug 2021Tumor resistance to apoptosis and the immunosuppressive tumor microenvironment are two major contributors to poor therapeutic responses during cancer intervention.... (Review)
Review
Tumor resistance to apoptosis and the immunosuppressive tumor microenvironment are two major contributors to poor therapeutic responses during cancer intervention. Pyroptosis, a lytic and inflammatory programmed cell death pathway distinct from apoptosis, has subsequently sparked notable interest among cancer researchers for its potential to be clinically harnessed and to address these problems. Recent evidence indicates that pyroptosis induction in tumor cells leads to a robust inflammatory response and marked tumor regression. Underlying its antitumor effect, pyroptosis is mediated by pore-forming gasdermin proteins that facilitate immune cell activation and infiltration through their release of pro-inflammatory cytokines and immunogenic material following cell rupture. Considering its inflammatory nature, however, aberrant pyroptosis may also be implicated in the formation of a tumor supportive microenvironment, as evidenced by the upregulation of gasdermin proteins in certain cancers. In this review, the molecular pathways leading to pyroptosis are introduced, followed by an overview of the seemingly entangled links between pyroptosis and cancer. We describe what is known regarding the impact of pyroptosis on anticancer immunity and give insight into the potential of harnessing pyroptosis as a tool and applying it to novel or existing anticancer strategies.
Topics: Animals; Biomarkers; Combined Modality Therapy; Disease Management; Disease Susceptibility; Gene Expression Regulation, Neoplastic; Humans; Immunity; Neoplasms; Pyroptosis; Signal Transduction; Treatment Outcome
PubMed: 34429144
DOI: 10.1186/s13046-021-02065-8 -
Frontiers in Immunology 2022Gasdermin D (GSDMD) serves as a key executor to trigger pyroptosis and is emerging as an attractive checkpoint in host defense, inflammatory, autoimmune diseases, and... (Review)
Review
Gasdermin D (GSDMD) serves as a key executor to trigger pyroptosis and is emerging as an attractive checkpoint in host defense, inflammatory, autoimmune diseases, and many other systemic diseases. Although canonical and non-canonical inflammasome-mediated classic GSDMD cleavage, GSDMD-NT migration to cell membrane, GSDMD-NT oligomerization, and pore forming have been well recognized, a few unique features of GSDMD in specific condition beyond its classic function, including non-lytic function of GSDMD, the modification and regulating mechanism of GSDMD signaling have also come to great attention and played a crucial role in biological processes and diseases. In the current review, we emphasized the GSDMD protein expression, stabilization, modification, activation, pore formation, and repair during pyroptosis, especially the regulation and modification of GSDMD signaling, such as GSDMD complex in polyubiquitination and non-pyroptosis release of IL-1β, ADP-riboxanation, NINJ1 in pore forming, GSDMD binding protein TRIM21, GSDMD succination, and Regulator-Rag-mTOR-ROS regulation of GSDMD. We also discussed the novel therapeutic strategies of targeting GSDMD and summarized recently identified inhibitors with great prospect.
Topics: Biological Phenomena; Inflammasomes; Intracellular Signaling Peptides and Proteins; Phosphate-Binding Proteins; Pyroptosis
PubMed: 35774778
DOI: 10.3389/fimmu.2022.893912 -
Trends in Cell Biology Sep 2017Pyroptosis is a form of lytic programmed cell death initiated by inflammasomes, which detect cytosolic contamination or perturbation. This drives activation of caspase-1... (Review)
Review
Pyroptosis is a form of lytic programmed cell death initiated by inflammasomes, which detect cytosolic contamination or perturbation. This drives activation of caspase-1 or caspase-11/4/5, which cleave gasdermin D, separating its N-terminal pore-forming domain (PFD) from the C-terminal repressor domain (RD). The PFD oligomerizes to form large pores in the membrane that drive swelling and membrane rupture. Gasdermin D is one of six (in humans) gasdermin family members; several other gasdermins have also been shown to form pores that cause pyroptosis after cleavage to activate their PFDs. One of these, gasdermin E, is activated by caspase-3 cleavage. We review our current understanding of pyroptosis as well as current knowledge of the gasdermin family.
Topics: Animals; Apoptosis; Caspases; Cell Membrane; Humans; Inflammasomes; Neoplasm Proteins; Pyroptosis
PubMed: 28619472
DOI: 10.1016/j.tcb.2017.05.005 -
Cell Death & Disease Apr 2020Many chemotherapy treatments induce apoptosis or pyroptosis through BAK/BAX-dependent mitochondrial pathway. BAK/BAX activation causes the mitochondrial outer membrane...
Many chemotherapy treatments induce apoptosis or pyroptosis through BAK/BAX-dependent mitochondrial pathway. BAK/BAX activation causes the mitochondrial outer membrane permeabilization (MOMP), which induces the activation of pro-apoptotic caspase cascade. GSDME cleavage by the pro-apoptotic caspases determines whether chemotherapy drug treatments induce apoptosis or pyroptosis, however, its regulation mechanisms are not clear. In this study, we showed that TNFα+CHX and navitoclax-induced cancer cell pyroptosis through a BAK/BAX-caspase-3-GSDME signaling pathway. GSDME knockdown inhibited the pyroptosis, suggesting the essential role of GSDME in this process. Interestingly, GSDME was found to be palmitoylated on its C-terminal (GSDME-C) during chemotherapy-induced pyroptosis, while 2-bromopalmitate (2-BP) could inhibit the GSDME-C palmitoylation and chemotherapy-induced pyroptosis. Mutation of palmitoylation sites on GSDME also diminished the pyroptosis induced by chemotherapy drugs. Moreover, 2-BP treatment increased the interaction between GSDME-C and GSDME-N, providing a potential mechanism of this function. Further studies indicated several ZDHHC proteins including ZDHHC-2,7,11,15 could interact with and palmitoylate GSDME. Our findings offered new targets to achieve the transformation between chemotherapy-induced pyroptosis and apoptosis.
Topics: Antineoplastic Agents; Caspase 3; HeLa Cells; Humans; Palmitates; Pyroptosis; Transfection
PubMed: 32332857
DOI: 10.1038/s41419-020-2476-2 -
Cell Death and Differentiation Aug 2021Renal tubular cell (RTC) death and inflammation contribute to the progression of obstructive nephropathy, but its underlying mechanisms have not been fully elucidated....
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.
Topics: Animals; Disease Models, Animal; Fibrosis; Humans; Inflammation; Kidney Diseases; Mice; Pore Forming Cytotoxic Proteins; Pyroptosis
PubMed: 33664482
DOI: 10.1038/s41418-021-00755-6 -
Frontiers in Immunology 2023In the working-age population worldwide, diabetic retinopathy (DR), a prevalent complication of diabetes, is the main cause of vision impairment. Chronic low-grade... (Review)
Review
In the working-age population worldwide, diabetic retinopathy (DR), a prevalent complication of diabetes, is the main cause of vision impairment. Chronic low-grade inflammation plays an essential role in DR development. Recently, concerning the pathogenesis of DR, the Nod-Like Receptor Family Pyrin Domain Containing 3 (NLRP3) inflammasome in retinal cells has been determined as a causal factor. In the diabetic eye, the NLRP3 inflammasome is activated by several pathways (such as ROS and ATP). The activation of NPRP3 leads to the secretion of inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18), and leads to pyroptosis, a rapid inflammatory form of lytic programmed cell death (PCD). Cells that undergo pyroptosis swell and rapture, releasing more inflammatory factors and accelerating DR progression. This review focuses on the mechanisms that activate NLRP3 inflammasome and pyroptosis leading to DR. The present research highlighted some inhibitors of NLRP3/pyroptosis pathways and novel therapeutic measures concerning DR treatment.
Topics: Humans; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Pyroptosis; Diabetic Retinopathy; Caspase 1; Inflammation; Diabetes Mellitus
PubMed: 37180116
DOI: 10.3389/fimmu.2023.1151185 -
Science (New York, N.Y.) Jul 2022Human NLRP1 (NACHT, LRR, and PYD domain-containing protein 1) is an innate immune sensor predominantly expressed in the skin and airway epithelium. Here, we report that...
Human NLRP1 (NACHT, LRR, and PYD domain-containing protein 1) is an innate immune sensor predominantly expressed in the skin and airway epithelium. Here, we report that human NLRP1 senses the ultraviolet B (UVB)- and toxin-induced ribotoxic stress response (RSR). Biochemically, RSR leads to the direct hyperphosphorylation of a human-specific disordered linker region of NLRP1 (NLRP1) by MAP3K20/ZAKα kinase and its downstream effector, p38. Mutating a single ZAKα phosphorylation site in NLRP1 abrogates UVB- and ribotoxin-driven pyroptosis in human keratinocytes. Moreover, fusing NLRP1 to CARD8, which is insensitive to RSR by itself, creates a minimal inflammasome sensor for UVB and ribotoxins. These results provide insight into UVB sensing by human skin keratinocytes, identify several ribotoxins as NLRP1 agonists, and establish inflammasome-driven pyroptosis as an integral component of the RSR.
Topics: Anisomycin; CARD Signaling Adaptor Proteins; Humans; Inflammasomes; Keratinocytes; MAP Kinase Kinase Kinases; Mutation; NLR Proteins; Neoplasm Proteins; Phosphorylation; Pyroptosis; Ribosomes; Stress, Physiological; Ultraviolet Rays
PubMed: 35857590
DOI: 10.1126/science.abl6324