{"title":"Gastrodenol suppresses NLRP3/GSDMD mediated pyroptosis and ameliorates inflammatory diseases","authors":"","doi":"10.1016/j.cellimm.2024.104888","DOIUrl":null,"url":null,"abstract":"<div><div>Pyroptosis, a form of inflammatory programmed cell death, plays a pivotal role in the pathogenesis of various diseases. This process is primarily mediated by the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3). Gastrodenol (Bismuth tripotassium dicitrate, GAS) is a mineral compound which is used to treat duodenal and gastric ulcers associated with Helicobacter pylori. In this study, GAS was found to exhibit protective effects against classical pyroptosis in macrophages. Specifically, GAS effectively inhibits the activation of the NLRP3 inflammasome, Gasdermin D (GSDMD)-mediated pyroptosis, and the secretion of pro-inflammatory cytokines. Mechanistically, GAS inhibited NLRP3 oligomerization and reduced the oligomerization of adaptor protein apoptosis-associated speck like protein containing a caspase activation and recruitment domain (ASC) by directly binding to NLRP3. The interaction between GAS and NLRP3 is primarily mediated through hydrogen bonding and hydrophobic forces. Hydrogen bonds are formed with PHE-727, LEU-723, and ASP-700. Remarkably, GAS treatment attenuated pyroptosis-mediated inflammatory diseases, including experimental autoimmune encephalomyelitis (EAE), lipopolysaccharide (LPS)-induced septic, and monosodium urate (MSU)-induced peritonitis in mice. To conclude, this is the first report that discovered clinical old medicine GAS as a potent inhibitor of pyroptosis and propose a novel therapeutic strategy for the prevention and treatment of NLRP3-GSDMD mediated diseases.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":null,"pages":null},"PeriodicalIF":3.7000,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cellular immunology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0008874924000911","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Pyroptosis, a form of inflammatory programmed cell death, plays a pivotal role in the pathogenesis of various diseases. This process is primarily mediated by the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3). Gastrodenol (Bismuth tripotassium dicitrate, GAS) is a mineral compound which is used to treat duodenal and gastric ulcers associated with Helicobacter pylori. In this study, GAS was found to exhibit protective effects against classical pyroptosis in macrophages. Specifically, GAS effectively inhibits the activation of the NLRP3 inflammasome, Gasdermin D (GSDMD)-mediated pyroptosis, and the secretion of pro-inflammatory cytokines. Mechanistically, GAS inhibited NLRP3 oligomerization and reduced the oligomerization of adaptor protein apoptosis-associated speck like protein containing a caspase activation and recruitment domain (ASC) by directly binding to NLRP3. The interaction between GAS and NLRP3 is primarily mediated through hydrogen bonding and hydrophobic forces. Hydrogen bonds are formed with PHE-727, LEU-723, and ASP-700. Remarkably, GAS treatment attenuated pyroptosis-mediated inflammatory diseases, including experimental autoimmune encephalomyelitis (EAE), lipopolysaccharide (LPS)-induced septic, and monosodium urate (MSU)-induced peritonitis in mice. To conclude, this is the first report that discovered clinical old medicine GAS as a potent inhibitor of pyroptosis and propose a novel therapeutic strategy for the prevention and treatment of NLRP3-GSDMD mediated diseases.
期刊介绍:
Cellular Immunology publishes original investigations concerned with the immunological activities of cells in experimental or clinical situations. The scope of the journal encompasses the broad area of in vitro and in vivo studies of cellular immune responses. Purely clinical descriptive studies are not considered.
Research Areas include:
• Antigen receptor sites
• Autoimmunity
• Delayed-type hypersensitivity or cellular immunity
• Immunologic deficiency states and their reconstitution
• Immunologic surveillance and tumor immunity
• Immunomodulation
• Immunotherapy
• Lymphokines and cytokines
• Nonantibody immunity
• Parasite immunology
• Resistance to intracellular microbial and viral infection
• Thymus and lymphocyte immunobiology
• Transplantation immunology
• Tumor immunity.