Upregulated PKM2 in Macrophages Exacerbates Experimental Arthritis via STAT1 Signaling
Upregulated PKM2 in Macrophages Exacerbates Experimental Arthritis via STAT1 Signaling
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巨噬细胞中 PKM2 上调通过 STAT1 信号传导加剧实验性关节炎
DOI：
10.4049/jimmunol.1901021
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发表时间：
2020-07-01
影响因子：
4.4
通讯作者：
Lu, Shemin
中科院分区：
文献类型：
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作者：
Xu, Jing;Jiang, Congshan;Lu, Shemin
最近的研究表明，类风湿性关节炎患者的糖代谢发生了改变。我们假设，PKM2作为糖酵解途径的关键调节酶，触发巨噬细胞(M Phi)的激活，从而导致关节炎进展过程中促炎细胞因子的产生。在本研究中，通过免疫荧光、Western blotting和定量RT-PCR发现，在关节炎大鼠的脾和滑膜组织中，PKM2在ED1阳性的M Phi中过表达。为了揭示PKM2的作用，用PKM2酶抑制剂紫草素或PKM2的RNA干扰质粒和阴性对照质粒分别经腹腔注射处理Dark Agti大鼠。注射。PKM2干预可从大体关节炎评分、中爪周长变化、滑膜炎及骨软骨破坏等方面减轻大鼠关节炎的严重程度，减少滑膜组织中ED1和p-STAT1阳性细胞的数量。在经典激活的大鼠和小鼠M Phi中，通过RNA干扰沉默PKM2导致通过STAT1信号产生的肿瘤坏死因子-α，n-1β减少。总的来说，PKM2在关节炎大鼠脾和滑膜组织ED1阳性的M Phi中高表达，并通过STAT1信号促进M Phi激活。PKM2可能是治疗类风湿性关节炎的一种有前途的选择性代谢靶分子。
Recent studies indicate that glucose metabolism is altered in rheumatoid arthritis. We hypothesize that Pkm2, as a key regulatory enzyme of glycolysis pathway, triggers the activation of macrophages (M phi), which results in proinflammatory cytokine production during the arthritis progress. In this study, Pkm2 was found to be overexpressed in ED1-positive M phi in spleens and synovial tissues from arthritic rats via immunofluorescence, Western blotting, and quantitative RT-PCR. To reveal the role of Pkm2, Dark Agouti rats were treated with either Pkm2 enzyme inhibitor shikonin or the RNA interference plasmids of Pkm2 and negative control plasmids, respectively, via i.p. injection. Pkm2 intervention could alleviate the severity of pristane-induced arthritis in aspects of the macroscopic arthritis score, perimeter changes of midpaw, and the synovitis and destruction of the bone and cartilage as well as reduce the ED1 and p-Stat1-positive cell population in rat synovial tissues. Silencing Pkm2 by RNA interference in classical activated rat and mouse M phi resulted in less Tnf-alpha, n-1 beta production via Stat1 signaling. Collectively, Pkm2 is highly expressed in ED1-positive M phi of spleens and synovial tissues from arthritic rats and promotes M phi activation via Stat1 signaling. Pkm2 might be a promising selective metabolic target molecule for rheumatoid arthritis treatment.