Cytokine tumor necrosis factor (TNF)-mediated macrophage polarization is important for inflammatory disease pathogenesis, but the mechanisms regulating polarization are not clear. We performed transcriptomic and epigenomic analysis of the TNF response in primary human macrophages and revealed late-phase activation of SREBP2, the master regulator of cholesterol biosynthesis genes. TNF stimulation extended the genomic profile of SREBP2 occupancy to include binding to and activation of inflammatory and interferon response genes independently of its functions in sterol metabolism. Genetic ablation of SREBP function shifted the balance of macrophage polarization from an inflammatory to a reparative phenotype in peritonitis and skin wound healing models. Genetic ablation of SREBP activity in myeloid cells or topical pharmacological inhibition of SREBP improved skin wound healing under homeostatic and chronic inflammatory conditions. Our results identify a function and mechanism of action for SREBPs in augmenting TNF-induced macrophage activation and inflammation and open therapeutic avenues for promoting wound repair.

中文翻译：

---

细胞因子TNF促进转录因子SREBP活性并与炎症基因结合，从而激活巨噬细胞并限制组织修复。

细胞因子肿瘤坏死因子（TNF）介导的巨噬细胞极化对于炎症性疾病的发病机制很重要，但调节极化的机制尚不清楚。我们对人类原发性巨噬细胞中的TNF反应进行了转录组学和表观基因组分析，并揭示了SREBP2的后期激活，SREBP2是胆固醇生物合成基因的主要调节剂。TNF刺激扩展了SREBP2的基因组分布，包括与炎症和干扰素反应基因的结合和活化，而与它在固醇代谢中的功能无关。SREBP功能的遗传消融将腹膜炎和皮肤伤口愈合模型中的巨噬细胞极化平衡从炎症转变为修复表型。遗传性消融髓样细胞中的SREBP活性或局部抑制SREBP可以改善在稳态和慢性炎症条件下的皮肤伤口愈合。我们的结果确定了SREBPs在增强TNF诱导的巨噬细胞活化和炎症中的功能和作用机制，并为促进伤口修复开辟了治疗途径。