冬凌草甲素通过抑制 PKM2/NLRP3 介导的巨噬细胞焦亡减轻肝缺血再灌注损伤。
Oridonin attenuates liver ischemia-reperfusion injury by suppressing PKM2/NLRP3-mediated macrophage pyroptosis.
机构信息
Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, China.
Department of Hepatobiliary Surgery, the People's Hospital of Tongnan District Chongqing City, China.
出版信息
Cell Immunol. 2024 Jul-Aug;401-402:104838. doi: 10.1016/j.cellimm.2024.104838. Epub 2024 May 23.
BACKGROUND
The NOD-like receptor protein 3 (NLRP3) mediated pyroptosis of macrophages is closely associated with liver ischemia reperfusion injury (IRI). As a covalent inhibitor of NLRP3, Oridonin (Ori), has strong anti-inflammasome effect, but its effect and mechanisms for liver IRI are still unknown.
METHODS
Mice and liver macrophages were treated with Ori, respectively. Co-IP and LC-MS/MS analysis of the interaction between PKM2 and NLRP3 in macrophages. Liver damage was detected using H&E staining. Pyroptosis was detected by WB, TEM, and ELISA.
RESULTS
Ori ameliorated liver macrophage pyroptosis and liver IRI. Mechanistically, Ori inhibited the interaction between pyruvate kinase M2 isoform (PKM2) and NLRP3 in hypoxia/reoxygenation（H/R）-induced macrophages, while the inhibition of PKM2/NLRP3 reduced liver macrophage pyroptosis and liver IRI.
CONCLUSION
Ori exerted protective effects on liver IRI via suppressing PKM2/NLRP3-mediated liver macrophage pyroptosis, which might become a potential therapeutic target in the clinic.
背景
NOD 样受体蛋白 3（NLRP3）介导的巨噬细胞焦亡与肝缺血再灌注损伤（IRI）密切相关。作为 NLRP3 的共价抑制剂，冬凌草甲素（Ori）具有很强的抗炎症小体作用，但它对肝 IRI 的作用及其机制尚不清楚。
方法
分别用 Ori 处理小鼠和肝巨噬细胞。用免疫共沉淀和 LC-MS/MS 分析巨噬细胞中 PKM2 与 NLRP3 的相互作用。用 H&E 染色检测肝损伤。用 WB、TEM 和 ELISA 检测焦亡。
结果
Ori 改善了肝巨噬细胞焦亡和肝 IRI。机制上，Ori 在缺氧/复氧（H/R）诱导的巨噬细胞中抑制了丙酮酸激酶 M2 同工型（PKM2）与 NLRP3 的相互作用，而 PKM2/NLRP3 的抑制减少了肝巨噬细胞焦亡和肝 IRI。
结论
Ori 通过抑制 PKM2/NLRP3 介导的肝巨噬细胞焦亡对肝 IRI 发挥保护作用，这可能成为临床治疗的一个潜在靶点。
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