Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Acta Pharmacol Sin. 2023 Jul;44(7):1404-1415. doi: 10.1038/s41401-022-01049-4. Epub 2023 Jan 31.
Myokines, which are recently identified cytokines secreted by skeletal muscle in response to stimulation, are crucial for the maintenance of liver function. Fulminant hepatitis (FH) is a life-threatening pathological condition with severe hepatic dysfunction. In this study, we investigated the role of meteorin-like (METRNL), a new myokine, in the pathogenesis of FH. We compared serum samples and liver tissues from FH patients and healthy controls and found that hepatic and serum METRNL levels were significantly increased in FH patients, and serum METRNL levels were related to disease severity in FH patients. We then established a concanavalin A-induced FH model in METRNL-overexpressing and control mice. We found that hepatic METRNL levels in FH mice were significantly increased, and METRNL in the liver was mainly derived from macrophages. In the cultured mouse macrophage line (RAW264.7 cells) and mouse primary peritoneal macrophages (PMs), METRNL overexpression significantly inhibited the release of the proinflammatory cytokines TNF and IL-1β. In METRNL-overexpressing mice, concanavalin A-induced liver injury was significantly ameliorated. Moreover, METRNL overexpression significantly reduced chemokine-dependent inflammatory cell infiltration into the liver. METRNL overexpression also suppressed liver CD4 T cell differentiation into Th 1 cells and inhibited the secretion of Th 1 cytokines. Taken together, these data suggest that METRNL overexpression effectively ameliorates FH. Therefore, METRNL may serve as a potential biomarker and therapeutic target for FH.
肌因子，是最近被鉴定出的骨骼肌在受到刺激时分泌的细胞因子，对于维持肝功能至关重要。暴发性肝炎（FH）是一种危及生命的严重肝功能障碍的病理状态。在这项研究中，我们研究了肌生成素样蛋白（METRNL）作为一种新的肌因子在 FH 发病机制中的作用。我们比较了 FH 患者和健康对照者的血清样本和肝组织，发现 FH 患者的肝和血清 METRNL 水平显著升高，并且 FH 患者的血清 METRNL 水平与疾病严重程度相关。然后，我们在 METRNL 过表达和对照小鼠中建立了伴刀豆球蛋白 A 诱导的 FH 模型。我们发现 FH 小鼠的肝 METRNL 水平显著升高，并且肝脏中的 METRNL 主要来源于巨噬细胞。在培养的小鼠巨噬细胞系（RAW264.7 细胞）和小鼠原代腹腔巨噬细胞（PMs）中，METRNL 过表达显著抑制促炎细胞因子 TNF 和 IL-1β的释放。在 METRNL 过表达小鼠中，伴刀豆球蛋白 A 诱导的肝损伤明显改善。此外，METRNL 过表达显著减少趋化因子依赖性炎症细胞浸润到肝脏。METRNL 过表达还抑制了肝 CD4 T 细胞向 Th1 细胞的分化，并抑制了 Th1 细胞因子的分泌。综上所述，这些数据表明 METRNL 过表达可有效改善 FH。因此，METRNL 可能是 FH 的潜在生物标志物和治疗靶点。
