Sepsis, a systemic immune syndrome caused by severe trauma or infection, poses a substantial threat to the health of patients worldwide. The progression of sepsis is heavily influenced by septic liver injury, which is triggered by infection and cytokine storms, and has a significant impact on the tolerance and prognosis of septic patients. The objective of our study is to elucidate the biological role and molecular mechanism of fibroblast growth factor 21 (FGF21) in the process of sepsis. This study was undertaken in an attempt to elucidate the function and molecular mechanism of FGF21 in therapy of sepsis. Serum concentrations of FGF21 were measured in sepsis patients and septic mice. Liver injury was compared between mice FGF21 knockout (KO) mice and wildtype (WT) mice. To assess the therapeutic potential, recombinant human FGF21 was administered to septic mice. Furthermore, the molecular mechanism of FGF21 was investigated in mice with myeloid-cell specific HIF-1α overexpression mice (LyzM-Cre) and myeloid-cell specific knockout mice (). Serum level of FGF21 was significantly increased in sepsis patients and septic mice. Through the use of recombinant human FGF21 (rhFGF21) and FGF21 KO mice, we found that FGF21 mitigated septic liver injury by inhibiting the initiation and propagation of inflammation. Treatment with rhFGF21 effectively suppressed the activation of proinflammatory macrophages by promoting macroautophagy/autophagy degradation of hypoxia-inducible factor-1α (HIF-1α). Importantly, the therapeutic effect of rhFGF21 against septic liver injury was nullified in LyzM-Cre mice and mice. Our findings demonstrate that FGF21 considerably suppresses inflammation upon septic liver injury through the autophagy/ HIF-1α axis.

中文翻译：

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FGF21 通过自噬/HIF-1α 轴抑制促炎巨噬细胞激活，从而改善脓毒性肝损伤

脓毒症是一种由严重创伤或感染引起的系统性免疫综合征，对全世界患者的健康构成重大威胁。脓毒症的进展很大程度上受到感染和细胞因子风暴引发的脓毒性肝损伤的影响，对脓毒症患者的耐受性和预后有显着影响。我们的研究目的是阐明成纤维细胞生长因子21（FGF21）在脓毒症过程中的生物学作用和分子机制。本研究旨在阐明FGF21在脓毒症治疗中的功能和分子机制。测量脓毒症患者和脓毒症小鼠的 FGF21 血清浓度。比较 FGF21 敲除 (KO) 小鼠和野生型 (WT) 小鼠的肝损伤。为了评估治疗潜力，将重组人 FGF21 给予脓毒症小鼠。此外，在骨髓细胞特异性 HIF-1α 过表达小鼠 (LyzM-Cre) 和骨髓细胞特异性基因敲除小鼠 () 中研究了 FGF21 的分子机制。脓毒症患者和脓毒症小鼠血清中 FGF21 水平显着升高。通过使用重组人 FGF21 (rhFGF21) 和 FGF21 KO 小鼠，我们发现 FGF21 通过抑制炎症的发生和传播来减轻脓毒性肝损伤。 rhFGF21 治疗通过促进缺氧诱导因子 1α (HIF-1α) 的巨自噬/自噬降解，有效抑制促炎巨噬细胞的活化。重要的是，rhFGF21 对化脓性肝损伤的治疗作用在 LyzM-Cre 小鼠和小鼠中无效。我们的研究结果表明，FGF21 通过自噬/ HIF-1α 轴显着抑制脓毒性肝损伤时的炎症。