Redox Biology (2021-01-01)

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

Journal volume & issue
Vol. 38
p. 101775

Abstract

Read online

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.

Keywords