期刊
ADVANCED SCIENCE
卷 8, 期 19, 页码 -出版社
WILEY
DOI: 10.1002/advs.202004162
关键词
atherosclerosis; PC4; SUB1; TLR2; TLR4; Toll-like receptor
资金
- National Natural Science Foundation of China [81960095]
- Chongqing Health Committee [2020FYYX047]
The study shows that TLR2 and TLR4 signaling plays a proinflammatory and proatherosclerotic role in atherosclerosis, primarily mediated by Sub1. Knockout of Sub1 promotes M2 macrophage polarization and cholesterol efflux, reducing atherosclerotic burden.
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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