Matrix metalloproteinase-12 produced by Ly6Clow macrophages prolongs the survival after myocardial infarction by preventing neutrophil influx

Akihiko Kubota; Akira Suto; Kotaro Suzuki; Yoshio Kobayashi; Hiroshi Nakajima

doi:10.1016/j.yjmcc.2019.04.007

Matrix metalloproteinase-12 produced by Ly6C^low macrophages prolongs the survival after myocardial infarction by preventing neutrophil influx

J Mol Cell Cardiol. 2019 Jun:131:41-52. doi: 10.1016/j.yjmcc.2019.04.007. Epub 2019 Apr 19.

Authors

Akihiko Kubota¹, Akira Suto², Kotaro Suzuki³, Yoshio Kobayashi¹, Hiroshi Nakajima⁴

Affiliations

¹ Department of Cardiovascular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
² Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan; Institute for Global Prominent Research, Chiba University, Chiba, Japan. Electronic address: suaki@faculty.chiba-u.jp.
³ Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan.
⁴ Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan. Electronic address: nakajimh@faculty.chiba-u.jp.

PMID: 31009606
DOI: 10.1016/j.yjmcc.2019.04.007

Abstract

Background: Various immune cells are involved in different phases of cardiac repair after myocardial infarction (MI). Especially, Ly6C^low M2-like macrophages (Ly6C^lo macrophages) are vital for cardiac repair after MI. However, the molecular mechanisms how Ly6C^lo macrophages promote wound healing after MI are still largely unknown.

Methods and results: Transcriptome analysis of Ly6C^lo macrophages and Ly6C^high M1-like macrophages (Ly6C^hi macrophages) harvested from the infarcted heart revealed that Ly6C^lo macrophages highly expressed matrix metalloproteinase (MMP)-12 mRNA compared to Ly6C^hi macrophages. MMP-12 expression was enhanced in the infarcted heart and preferentially observed in Ly6C^lo macrophages. Importantly, the survival rate and cardiac function after MI were significantly impaired in MMP-12-deficient (mmp12^-/-) mice compared with those in wild-type mice. In addition, the extent of myocardial fibrosis and the number of myofibroblasts in the infarct area were decreased in mmp12^-/- mice. MMP-9 expression and neutrophils, which are the major cellular source of MMP-9, in the infarcted heart were increased in mmp12^-/- mice. Moreover, mRNA expression of neutrophil-attracting chemokines including CXCL1, CXCL2, and CXCL5 was significantly higher in mmp12^-/- mice. Consistently, treatment with anti-CXCR2 antibody significantly decreased neutrophil numbers and MMP-9 expression in the infarcted heart in mmp12^-/- mice. Finally, the administration of recombinant MMP-12 into the infarcted heart decreased neutrophil numbers in the infarcted heart and promoted wound healing in both wild-type mice and mmp12^-/- mice.

Conclusion: MMP-12 produced by Ly6C^lo macrophages improves the survival after MI possibly through the promotion of wound healing by reducing neutrophil infiltration.

Keywords: MMP-12; Myocardial fibrosis; Myocardial infarction; Myocardial inflammation.

Publication types

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

MeSH terms

Animals
Antibodies, Neutralizing / therapeutic use
Echocardiography
Flow Cytometry
Inflammation / metabolism
Macrophages / drug effects
Macrophages / metabolism*
Male
Matrix Metalloproteinase 12 / therapeutic use*
Matrix Metalloproteinase 2 / metabolism
Matrix Metalloproteinase 9 / metabolism
Mice
Mice, Inbred C57BL
Myocardial Infarction / drug therapy*
Myocardial Infarction / metabolism
Myocardium / metabolism
Neutrophils / drug effects
Neutrophils / metabolism
Sequence Analysis, RNA

Substances

Antibodies, Neutralizing
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9
Matrix Metalloproteinase 12