p38α in macrophages aggravates arterial endothelium injury by releasing IL-6 through phosphorylating megakaryocytic leukemia 1

Meng Zhang; Jianing Gao; Xuyang Zhao; Mingming Zhao; Dong Ma; Xinhua Zhang; Dongping Tian; Bing Pan; Xiaoxiang Yan; Jianwei Wu; Xia Meng; Huiyong Yin; Lemin Zheng

doi:10.1016/j.redox.2020.101775

p38α in macrophages aggravates arterial endothelium injury by releasing IL-6 through phosphorylating megakaryocytic leukemia 1

Redox Biol. 2021 Jan:38:101775. doi: 10.1016/j.redox.2020.101775. Epub 2020 Nov 1.

Authors

Meng Zhang¹, Jianing Gao², Xuyang Zhao³, Mingming Zhao⁴, Dong Ma⁵, Xinhua Zhang⁶, Dongping Tian⁷, Bing Pan⁸, Xiaoxiang Yan⁹, Jianwei Wu¹⁰, Xia Meng¹¹, Huiyong Yin¹², Lemin Zheng¹³

Affiliations

¹ The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences of Ministry of Education, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Health Science Center, Peking University, Beijing, 100191, China. Electronic address: zhangmeng.118@163.com.
² The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences of Ministry of Education, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Health Science Center, Peking University, Beijing, 100191, China. Electronic address: gaojianing27@126.com.
³ The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences of Ministry of Education, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Health Science Center, Peking University, Beijing, 100191, China. Electronic address: xyzhao@hsc.pku.edu.cn.
⁴ The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences of Ministry of Education, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Health Science Center, Peking University, Beijing, 100191, China. Electronic address: pkuzhao@163.com.
⁵ School of Public Health, North China University of Science and Technology, 21 Bohai Avenue, Caofeidian New City, Tangshan, 063210, Hebei, China. Electronic address: mamamadong@163.com.
⁶ Department of Biochemistry and Molecular Biology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education. Hebei Medical University, No. 361 Zhongshan E Rd, Shijiazhuang, 050017, Hebei, China. Electronic address: xiaomifeng800815@126.com.
⁷ Dept. of Pathology, Shantou University Medical College, No.22 Xinling Road, Shantou, 515041, Guangdong, China. Electronic address: dp_tian@163.com.
⁸ The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences of Ministry of Education, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Health Science Center, Peking University, Beijing, 100191, China. Electronic address: panbintz@163.com.
⁹ Department of Cardiology, Rui Jin Hospital, Shanghai Jiaotong University School of Medicine, China; Institute of Cardiovascular Diseases, Shanghai Jiaotong University School of Medicine, China. Electronic address: cardexyanxx@hotmail.com.
¹⁰ Beijing Tiantan Hospital, China National Clinical Research Center for Neurological Diseases, Advanced Innovation Center for Human Brain Protection, The Capital Medical University, Beijing, 100050, China. Electronic address: 271168399@qq.com.
¹¹ Beijing Tiantan Hospital, China National Clinical Research Center for Neurological Diseases, Advanced Innovation Center for Human Brain Protection, The Capital Medical University, Beijing, 100050, China. Electronic address: mengxia45@163.com.
¹² CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health (SINH), Chinese Academy of Sciences (CAS), Shanghai, 200031, China, University of the Chinese Academy of Sciences, CAS, Beijing, China, Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing, China, School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. Electronic address: hyyin@sibs.ac.cn.
¹³ The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences of Ministry of Education, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Health Science Center, Peking University, Beijing, 100191, China; Beijing Tiantan Hospital, China National Clinical Research Center for Neurological Diseases, Advanced Innovation Center for Human Brain Protection, The Capital Medical University, Beijing, 100050, China. Electronic address: zhengl@bjmu.edu.cn.

Abstract

Background: Macrophages regulate the inflammatory response and affect re-endothelialization. Inflammation and macrophages play important roles in promoting tissue repair, but p38α mitogen-activated protein kinase's role in re-endothelialization is unknown.

Methods and results: Wire injuries of carotid arteries and Evans blue staining were performed in macrophage-specific p38α-knockout (p38α^fl/flLysMCre^+/-) mice and control mice (p38α^fl/fl). Re-endothelialization of the carotid arteries at 3, 5 and 7 days was significantly promoted in p38α^fl/flLysMCre^+/- mice. In vitro experiments indicated that both the proliferation and migration of endothelial cells were enhanced in conditioned medium from peritoneal macrophages of p38α^fl/flLysMCre^+/- mice. Interleukin-6 (IL-6) level was decreased significantly in macrophages of p38α^fl/flLysMCre^+/- mice and an IL-6-neutralizing antibody promoted endothelial cell migration in vitro and re-endothelialization in p38α^fl/fl mice in vivo. Phosphoproteomics revealed that the phosphorylation level of S544/T545/S549 sites in megakaryocytic leukemia 1 (MKL1) was decreased in p38α^fl/flLysMCre^+/- mice. The mutation of either S544/S549 or T545/S549 sites could reduce the expression of IL-6 and the inhibition of MKL1 reduced the expression of IL-6 in vitro and promoted re-endothelialization in vivo.

Conclusion: p38α in macrophages aggravates injury of arteries by phosphorylating MKL1, and increasing IL-6 expression after vascular injury.

Keywords: Endothelial cell; Interleukin-6; Megakaryocytic leukemia 1; Re-endothelialization; p38.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Endothelial Cells
Endothelium, Vascular / pathology*
Interleukin-6
Intracellular Signaling Peptides and Proteins*
Macrophages*
Mice
Phosphorylation
Vascular System Injuries*
p38 Mitogen-Activated Protein Kinases*

Substances

Interleukin-6
Intracellular Signaling Peptides and Proteins
megakaryocytic acute leukemia protein, mouse
p38 Mitogen-Activated Protein Kinases