11,12-EET Regulates PPAR-γ Expression to Modulate TGF-β-Mediated Macrophage Polarization

Abstract

Macrophages are highly plastic immune cells that can be reprogrammed to pro-inflammatory or pro-resolving phenotypes by different stimuli and cell microenvironments. This study set out to assess gene expression changes associated with the transforming growth factor (TGF)-β-induced polarization of classically activated macrophages into a pro-resolving phenotype. Genes upregulated by TGF-β included Pparg; which encodes the transcription factor peroxisome proliferator-activated receptor (PPAR)-γ, and several PPAR-γ target genes. TGF-β also increased PPAR-γ protein expression via activation of the Alk5 receptor to increase PPAR-γ activity. Preventing PPAR-γ activation markedly impaired macrophage phagocytosis. TGF-β repolarized macrophages from animals lacking the soluble epoxide hydrolase (sEH); however, it responded differently and expressed lower levels of PPAR-γ-regulated genes. The sEH substrate 11,12-epoxyeicosatrienoic acid (EET), which was previously reported to activate PPAR-γ, was elevated in cells from sEH−/− mice. However, 11,12-EET prevented the TGF-β-induced increase in PPAR-γ levels and activity, at least partly by promoting proteasomal degradation of the transcription factor. This mechanism is likely to underlie the impact of 11,12-EET on macrophage activation and the resolution of inflammation.