Oridonin attenuates liver ischemia–reperfusion injury by suppressing PKM2/NLRP3-mediated macrophage pyroptosis

IF 3.7 4区医学 Q2 CELL BIOLOGY Cellular immunology Pub Date : 2024-05-23 DOI:10.1016/j.cellimm.2024.104838

Xin-yi Wu , Min-jie Zhao , Wei Liao , Tao Liu , Jun-Yan Liu , Jun-hua Gong , Xing Lai , Xue-song Xu

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Abstract

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.

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奥利多宁通过抑制 PKM2/NLRP3 介导的巨噬细胞热解作用减轻肝脏缺血再灌注损伤

背景NOD样受体蛋白3（NLRP3）介导的巨噬细胞热凋亡与肝脏缺血再灌注损伤（IRI）密切相关。作为 NLRP3 的共价抑制剂，Oridonin（Ori）具有很强的抗炎作用，但其对肝脏 IRI 的影响和机制尚不清楚。方法分别用 Ori 处理小鼠和肝巨噬细胞，对巨噬细胞中 PKM2 和 NLRP3 的相互作用进行 Co-IP 和 LC-MS/MS 分析。用 H&E 染色法检测肝损伤。结果Ori改善了肝巨噬细胞的脓毒症和肝脏IRI。从机理上讲，Ori抑制了缺氧/复氧（H/R）诱导的巨噬细胞中丙酮酸激酶M2同工酶（PKM2）和NLRP3之间的相互作用，而抑制PKM2/NLRP3则减轻了肝巨噬细胞的脓毒症和肝脏IRI。结论Ori通过抑制PKM2/NLRP3介导的肝巨噬细胞脓毒症对肝脏IRI具有保护作用，这可能成为临床上的一个潜在治疗靶点。

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来源期刊

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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