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.

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.

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