11,12-EET Regulates PPAR-gamma Expression to Modulate TGF-beta-Mediated Macrophage Polarization

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)-beta-induced polarization of classically activated macrophages into a pro-resolving phenotype. Genes upregulated by TGF-beta included Pparg; which encodes the transcription factor peroxisome proliferator-activated receptor (PPAR)-gamma, and several PPAR-gamma target genes. TGF-beta also increased PPAR-gamma protein expression via activation of the Alk5 receptor to increase PPAR-gamma activity. Preventing PPAR-gamma activation markedly impaired macrophage phagocytosis. TGF-beta repolarized macrophages from animals lacking the soluble epoxide hydrolase (sEH); however, it responded differently and expressed lower levels of PPAR-gamma-regulated genes. The sEH substrate 11,12-epoxyeicosatrienoic acid (EET), which was previously reported to activate PPAR-gamma, was elevated in cells from sEH(-/-) mice. However, 11,12-EET prevented the TGF-beta-induced increase in PPAR-gamma 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.