GSE129202
TNF promotes SREBP activity to regulate macrophage polarization and tissue repair [ChIP-seq]
TNF-mediated macrophage polarization is important for inflammatory disease  pathogenesis, but mechanisms that regulate polarization are not well understood.  Transcriptomic and epigenomic analysis of the TNF response in primary human  macrophages 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 M1 to an M2-like  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 new function and mechanism of action for SREBP2 in  augmenting TNF-induced M1 macrophage polarization and inflammation, and open  therapeutic avenues for promoting wound repair. Overall design: Analysis of transcriptional changes in human macrophages stimulated with or without TNF