FGF21 promotes the resolution of inflammation through the ALOX15/SPM pathway in acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is a life-threatening clinical condition associated with high morbidity and mortality, mainly resulting from excessive inflammation and failure of inflammation-resolving mechanisms. Fibroblast growth factor 21 (FGF21) is a metabolic regulator possessing anti-inflammatory properties; however, its role and mechanism in the resolution of inflammation remain unclear. This study showed that FGF21 facilitated the resolution of inflammation by promoting the production of specialized pro-resolving mediators (SPMs) in a mouse model of LPS-induced lung injury. SPMs, generated from arachidonic acid, docosahexaenoic acid, and eicosapentaenoic acid through enzymatic conversion by ALOX15 and related enzymes, exerted anti-inflammatory and pro-resolving effects by binding to their specific receptors. Furthermore, FGF21 was secreted by alveolar macrophages and acted in an autocrine manner to induce their polarization toward the M2 phenotype. Liquid chromatography-mass spectrometry revealed that FGF21 upregulated SPM production during the resolution phase by enhancing the expression of ALOX15 and SPM receptors on M2-polarized resident alveolar macrophages, thereby promoting the resolution of inflammation and attenuating lung injury. These findings provide new mechanistic insights into the resolution of ARDS.