Li_2024_iScience_27_110938

Fatty acid metabolites, produced by cytochrome P450 enzymes and soluble epoxide hydrolase (sEH), regulate inflammation. Here, we report that the transforming growth factor beta (TGF-beta)-induced polarization of macrophages to a pro-resolving phenotype requires Alk5 and Smad2 activation to increase sEH expression and activity. Macrophages lacking sEH showed impaired repolarization, reduced phagocytosis, and maintained a pro-inflammatory gene expression profile. 11,12-Epoxyeicosatrienoic acid (EET) was one altered metabolite in sEH(-/-) macrophages and mimicked the effect of sEH deletion on gene expression. Notably, 11,12-EET also reduced Alk5 expression, inhibiting TGF-beta-induced Smad2 phosphorylation by triggering the cytosolic translocation of the E3 ligase Smurf2. These findings suggest that sEH expression is controlled by TGF-beta and that sEH activity, which lowers 11,12-EET levels and promotes TGF-beta signaling by metabolizing 11,12-EET to prevent Alk5 degradation. Thus, an autocrine loop between sEH/11,12-EET and TGF-beta1 regulates macrophage function.