The Transcription Factor SUB1 Is a Master Regulator of the Macrophage TLR Response in Atherosclerosis
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 gen...
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2021-10-01
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doaj-ac5a4d8f547b4149a51d13c6b830c14a2021-10-08T09:03:07ZengWileyAdvanced Science2198-38442021-10-01819n/an/a10.1002/advs.202004162The Transcription Factor SUB1 Is a Master Regulator of the Macrophage TLR Response in AtherosclerosisRongzhong Huang0Zicheng Hu1Xiaorui Chen2Yu Cao3Hongrong Li4Hong Zhang5Yongyong Li6Liwen Liang7Yuxing Feng8Ying Wang9Wenhua Su10Zerui Kong11ND Melgiri12Lihong Jiang13Xingsheng Li14Jianlin Du15Yunqing Chen16Department of Geriatric Medicine The Second Affiliated Hospital of Chongqing Medical University Chongqing 400010 ChinaInstitute of Ultrasound Imaging The Second Affiliated Hospital of Chongqing Medical University Chongqing 400010 ChinaDepartment of Pulmonary and Critical Care Medicine The Second Affiliated Hospital of Chongqing Medical University Chongqing 400010 ChinaDepartment of Cardiothoracic Surgery The First People's Hospital of Yunnan Province Kunming 650032 ChinaDepartment of Cardiothoracic Surgery The First People's Hospital of Yunnan Province Kunming 650032 ChinaDepartment of Cardiology The First People's Hospital of Yunnan Province Kunming 650032 ChinaDepartment of Geriatric Medicine The Second Affiliated Hospital of Chongqing Medical University Chongqing 400010 ChinaDepartment of Cardiology The First People's Hospital of Yunnan Province Kunming 650032 ChinaDepartment of Rehabilitation and Pain Medicine The Ninth People's Hospital of Chongqing Chongqing 400700 ChinaDepartment of Rehabilitation Medicine The Second Affiliated Hospital of Chongqing Medical University Chongqing 400010 ChinaDepartment of Cardiology The First People's Hospital of Yunnan Province Kunming 650032 ChinaDepartment of Cardiothoracic Surgery The Affiliated Yan An Hospital of Kunming Medical University Kunming 650000 ChinaImpactys Foundation for Biomedical Research San Diego CA 92121 USADepartment of Cardiothoracic Surgery The First People's Hospital of Yunnan Province Kunming 650032 ChinaDepartment of Geriatric Medicine The Second Affiliated Hospital of Chongqing Medical University Chongqing 400010 ChinaDepartment of Cardiology The Second Affiliated Hospital of Chongqing Medical University Chongqing 400010 ChinaDepartment of Cardiology The Second Affiliated Hospital of Chongqing Medical University Chongqing 400010 ChinaAbstract 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.https://doi.org/10.1002/advs.202004162atherosclerosisPC4SUB1TLR2TLR4, Toll‐like receptor |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Rongzhong Huang Zicheng Hu Xiaorui Chen Yu Cao Hongrong Li Hong Zhang Yongyong Li Liwen Liang Yuxing Feng Ying Wang Wenhua Su Zerui Kong ND Melgiri Lihong Jiang Xingsheng Li Jianlin Du Yunqing Chen |
spellingShingle |
Rongzhong Huang Zicheng Hu Xiaorui Chen Yu Cao Hongrong Li Hong Zhang Yongyong Li Liwen Liang Yuxing Feng Ying Wang Wenhua Su Zerui Kong ND Melgiri Lihong Jiang Xingsheng Li Jianlin Du Yunqing Chen The Transcription Factor SUB1 Is a Master Regulator of the Macrophage TLR Response in Atherosclerosis Advanced Science atherosclerosis PC4 SUB1 TLR2 TLR4, Toll‐like receptor |
author_facet |
Rongzhong Huang Zicheng Hu Xiaorui Chen Yu Cao Hongrong Li Hong Zhang Yongyong Li Liwen Liang Yuxing Feng Ying Wang Wenhua Su Zerui Kong ND Melgiri Lihong Jiang Xingsheng Li Jianlin Du Yunqing Chen |
author_sort |
Rongzhong Huang |
title |
The Transcription Factor SUB1 Is a Master Regulator of the Macrophage TLR Response in Atherosclerosis |
title_short |
The Transcription Factor SUB1 Is a Master Regulator of the Macrophage TLR Response in Atherosclerosis |
title_full |
The Transcription Factor SUB1 Is a Master Regulator of the Macrophage TLR Response in Atherosclerosis |
title_fullStr |
The Transcription Factor SUB1 Is a Master Regulator of the Macrophage TLR Response in Atherosclerosis |
title_full_unstemmed |
The Transcription Factor SUB1 Is a Master Regulator of the Macrophage TLR Response in Atherosclerosis |
title_sort |
transcription factor sub1 is a master regulator of the macrophage tlr response in atherosclerosis |
publisher |
Wiley |
series |
Advanced Science |
issn |
2198-3844 |
publishDate |
2021-10-01 |
description |
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. |
topic |
atherosclerosis PC4 SUB1 TLR2 TLR4, Toll‐like receptor |
url |
https://doi.org/10.1002/advs.202004162 |
work_keys_str_mv |
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