11,12-EET Regulates PPAR-γ Expression to Modulate TGF-β-Mediated Macrophage Polarization.
Xiaoming LiSebastian KempfStefan GüntherJiong HuIngrid FlemingPublished in: Cells (2023)
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.
Keyphrases
- transforming growth factor
- insulin resistance
- transcription factor
- epithelial mesenchymal transition
- gene expression
- fatty acid
- adipose tissue
- type diabetes
- genome wide identification
- skeletal muscle
- metabolic syndrome
- binding protein
- long non coding rna
- diabetic rats
- high fat diet induced
- cell therapy
- anti inflammatory
- bioinformatics analysis
- drug induced
- stress induced
- tyrosine kinase
- amino acid