Li Bo, Li Jiayu, Zhu Zexiang, Tang Yong, Zhou Yun, Du Geshu, Li Xing
Department of Critical Care Medicine, Changsha Hospital of Traditional Chinese Medicine (Changsha No. 8 Hospital), Changsha City, Hunan Province, PR China.
Department of Acupuncture, Moxibustion & rehabilitation, Changsha Hospital of Traditional Chinese Medicine (Changsha No. 8 Hospital), Changsha City, Hunan Province, PR China.
Cell Death Dis. 2025 Aug 19;16(1):628. doi: 10.1038/s41419-025-07962-w.
M1 macrophage polarization plays a key role in the onset and progression of sepsis. Fibroblast growth factor 15 (FGF15) suppresses septic inflammation through its FGF receptor 4 (FGFR4); however, the underlying mechanisms are largely unclear. In this study, we evaluated the anti-inflammatory effects of recombinant FGF15 (rFGF15) in cecal ligation and puncture (CLP)-induced septic mice in vivo, as well as lipopolysaccharide (LPS)-stimulated mouse bone marrow-derived macrophages (BMDMs) and RAW264.7 macrophages in vitro. We observed that rFGF15 suppressed M1 macrophage polarization and associated inflammatory responses in both CLP-induced septic mice and LPS-stimulated BMDMs and RAW264.7 macrophages. Additionally, macrophage-depleted CLP mice transplanted with LPS-stimulated BMDMs pre-treated with rFGF15 exhibited reduced multi-organ inflammation and enhanced survival compared to those receiving LPS-stimulated BMDMs without rFGF15 treatment. Mechanistically, FGF15 activated the neurofibromin 2 (NF2)-Hippo pathway through FGFR4, leading to the inhibition of glycolysis, lactate production, and histone H3K18 lactylation. This led to reduced expression of interferon regulatory factor 7 (Irf7), a key regulator of type I interferon responses. In conclusion, FGF15 suppresses M1 macrophage polarization and associated inflammatory responses in sepsis by activating the NF2-Hippo pathway, thereby inhibiting H3K18 lactylation-driven Irf7 expression. FGF15 holds promise as a potential innovative therapy for sepsis.
M1巨噬细胞极化在脓毒症的发生和发展中起关键作用。成纤维细胞生长因子15（FGF15）通过其FGF受体4（FGFR4）抑制脓毒症炎症；然而，其潜在机制在很大程度上尚不清楚。在本研究中，我们评估了重组FGF15（rFGF15）在体内对盲肠结扎和穿刺（CLP）诱导的脓毒症小鼠以及体外对脂多糖（LPS）刺激的小鼠骨髓来源巨噬细胞（BMDM）和RAW264.7巨噬细胞的抗炎作用。我们观察到，rFGF15在CLP诱导的脓毒症小鼠以及LPS刺激的BMDM和RAW264.7巨噬细胞中均抑制M1巨噬细胞极化和相关炎症反应。此外，与接受未经rFGF15处理的LPS刺激的BMDM的小鼠相比，移植经rFGF15预处理的LPS刺激的BMDM的巨噬细胞耗竭的CLP小鼠表现出多器官炎症减轻和存活率提高。机制上，FGF15通过FGFR4激活神经纤维瘤蛋白2（NF2）-Hippo通路，导致糖酵解、乳酸生成和组蛋白H3K18乳酸化受到抑制。这导致I型干扰素反应的关键调节因子干扰素调节因子7（Irf7）的表达降低。总之，FGF15通过激活NF2-Hippo通路抑制脓毒症中M（1）巨噬细胞极化和相关炎症反应，从而抑制H3K18乳酸化驱动的Irf7表达。FGF15有望成为脓毒症的一种潜在创新疗法。
