Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, 60596 Frankfurt am Main, Germany.
Max Planck Institute for Heart and Lung Research, Bioinformatics and Deep Sequencing Platform, 61231 Bad Nauheim, Germany.
Cells. 2023 Feb 23;12(5):700. doi: 10.3390/cells12050700.
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 ; 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.
巨噬细胞是高度可塑性的免疫细胞，可通过不同的刺激和细胞微环境重新编程为促炎或促解决的表型。本研究旨在评估与转化生长因子 (TGF)-β诱导经典激活的巨噬细胞向促解决表型极化相关的基因表达变化。TGF-β上调的基因包括 ; 其编码转录因子过氧化物酶体增殖物激活受体 (PPAR)-γ，和几个 PPAR-γ 靶基因。TGF-β 还通过激活 Alk5 受体增加 PPAR-γ 蛋白表达，从而增加 PPAR-γ 活性。阻止 PPAR-γ 激活显著损害巨噬细胞吞噬作用。TGF-β 使缺乏可溶性环氧化物水解酶 (sEH)的动物中的巨噬细胞重新极化；然而，它的反应不同，表达的 PPAR-γ 调节基因水平较低。先前报道过激活 PPAR-γ 的 sEH 底物 11,12-环氧二十碳三烯酸 (EET)在 sEH 小鼠的细胞中升高。然而，11,12-EET 阻止了 TGF-β 诱导的 PPAR-γ 水平和活性的增加，至少部分是通过促进转录因子的蛋白酶体降解来实现的。这种机制可能是 11,12-EET 对巨噬细胞激活和炎症消退的影响的基础。
