Gastrodenol suppresses NLRP3/GSDMD mediated pyroptosis and ameliorates inflammatory diseases

IF 3.7 4区 医学 Q2 CELL BIOLOGY Cellular immunology Pub Date : 2024-11-01 DOI:10.1016/j.cellimm.2024.104888
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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.
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Gastrodenol 可抑制 NLRP3/GSDMD 介导的脓毒症,改善炎症性疾病
裂解病是一种炎症性程序性细胞死亡,在各种疾病的发病机制中起着关键作用。这一过程主要由核苷酸结合寡聚化结构域样受体家族含吡啶结构域蛋白 3(NLRP3)介导。Gastrodenol(枸橼酸三钾铋,GAS)是一种矿物质化合物,用于治疗幽门螺旋杆菌引起的十二指肠和胃溃疡。这项研究发现,GAS 对巨噬细胞中的典型热蛋白沉积具有保护作用。具体来说,GAS 能有效抑制 NLRP3 炎性体的活化、Gasdermin D(GSDMD)介导的化脓作用以及促炎细胞因子的分泌。从机理上讲,GAS 通过直接与 NLRP3 结合,抑制了 NLRP3 的寡聚化,并减少了含有 Caspase 激活和招募结构域(ASC)的适应蛋白凋亡相关斑点样蛋白的寡聚化。GAS 与 NLRP3 之间的相互作用主要是通过氢键和疏水作用力介导的。氢键与 PHE-727、LEU-723 和 ASP-700 形成。值得注意的是,GAS 治疗可减轻热蛋白酶介导的炎症性疾病,包括实验性自身免疫性脑脊髓炎(EAE)、脂多糖(LPS)诱导的败血症和单钠尿酸盐(MSU)诱导的小鼠腹膜炎。总之,这是首次报道发现临床老药 GAS 是一种有效的热蛋白沉积抑制剂,并为预防和治疗 NLRP3-GSDMD 介导的疾病提出了一种新的治疗策略。
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来源期刊
Cellular immunology
Cellular immunology 生物-免疫学
CiteScore
8.20
自引率
2.30%
发文量
102
审稿时长
30 days
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.
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