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

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 (p38αfl/flLysMCre+/-) mice and control mice (p38αfl/fl). Re-endothelialization of the carotid arteries at 3, 5 and 7 days was significantly promoted in p38αfl/flLysMCre+/- mice. In vitro experiments indicated that both the proliferation and migration of endothelial cells were enhanced in conditioned medium from peritoneal macrophages of p38αfl/flLysMCre+/- mice. Interleukin-6 (IL-6) level was decreased significantly in macrophages of p38αfl/flLysMCre+/- mice and an IL-6-neutralizing antibody promoted endothelial cell migration in vitro and re-endothelialization in p38αfl/fl mice in vivo. Phosphoproteomics revealed that the phosphorylation level of S544/T545/S549 sites in megakaryocytic leukemia 1 (MKL1) was decreased in p38αfl/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.

• Authors: 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
• Journal: Redox biology (Redox Biol) Vol. 38 Pg. 101775 (01 2021) ISSN: 2213-2317 [Electronic] Netherlands
• PMID: 33171330 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.

Chemical References

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

Topics

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