| Summary: | Abstract Toll‐like receptor 2 and 4 (TLR2, TLR4) signaling is implicated in atherosclerotic plaque formation. The two‐stage master regulator Virtual Inference of Protein‐activity by Enriched Regulon (VIPER) analysis of macrophage TLR2 and TLR4 signature genes integrated with coexpression network genes derived from 371 patient‐derived carotid specimens identifies activated RNA polymerase II transcriptional coactivator p15 (SUB1/Sub1, PC4) as a master regulon in the atherogenic TLR response. It is found that TLR2 and TLR4 signaling is proinflammatory and proatherosclerotic in chow‐fed apolipoprotein E‐deficient (ApoE−/−) mice. Through transgenic myeloid‐specific Sub1 knockout in ApoE−/− mice, it is discovered that these proatherosclerotic effects of TLR2 and TLR4 signaling are mediated by Sub1. Sub1 knockout in macrophages enhances anti‐inflammatory M2 macrophage polarization and cholesterol efflux. Irradiated low density lipoprotein receptor‐deficient (Ldlr−/−) mice transplanted with Sub1−/− murine bone marrow display reduced atherosclerosis. Promoter analysis reveals Sub1‐dependent activation of interferon regulatory factor 1 (Irf1) transcription in a casein kinase 2 (Ck2)‐dependent manner, and Sub1‐knockout macrophages display decreased Irf1 expression. Artificial Irf1 overexpression in Sub1‐knockout macrophages enhances proinflammatory M1 skewing and lowers cholesterol clearance. In conclusion, the TLR master regulon Sub1, and its downstream effect on the transcription factor Irf1, promotes a proinflammatory M1 macrophage phenotype and enhances atherosclerotic burden in vivo.
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