A regulatory loop involving the cytochrome P450-soluble epoxide hydrolase axis 
and TGF-β signaling

Li, Xiaoming; Kempf, Sebastian; Lagos, Fredy Delgado; Ukan, Ueruen; Popp, Ruediger; Hu, Jiong; Froemel, Timo; Guenther, Stefan; Weigert, Andreas; Fleming, Ingrid

doi:10.1016/j.isci.2024.110938

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A regulatory loop involving the cytochrome P450-soluble epoxide hydrolase axis and TGF-β signaling

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Guenther, Stefan
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Citation

Li, X., Kempf, S., Lagos, F. D., Ukan, U., Popp, R., Hu, J., et al. (2024). A regulatory loop involving the cytochrome P450-soluble epoxide hydrolase axis and TGF-β signaling. ISCIENCE, 27(10): 110938. doi:10.1016/j.isci.2024.110938.

Cite as: https://hdl.handle.net/21.11116/0000-0010-08D5-5

Abstract

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-beta 1 regulates macrophage function.