Journal of molecular and cellular cardiology · 2019
Matrix metalloproteinase-12 produced by Ly6Clow macrophages prolongs the survival after myocardial infarction by preventing neutrophil influx.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Kubota Akihiko, Suto Akira, Suzuki Kotaro, Kobayashi Yoshio, Nakajima Hiroshi
Аннотация
BACKGROUND: Various immune cells are involved in different phases of cardiac repair after myocardial infarction (MI). Especially, Ly6Clow M2-like macrophages (Ly6Clo macrophages) are vital for cardiac repair after MI. However, the molecular mechanisms how Ly6Clo macrophages promote wound healing after MI are still largely unknown.
METHODS AND RESULTS: Transcriptome analysis of Ly6Clo macrophages and Ly6Chigh M1-like macrophages (Ly6Chi macrophages) harvested from the infarcted heart revealed that Ly6Clo macrophages highly expressed matrix metalloproteinase (MMP)-12 mRNA compared to Ly6Chi macrophages. MMP-12 expression was enhanced in the infarcted heart and preferentially observed in Ly6Clo 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 Ly6Clo macrophages improves the survival after MI possibly through the promotion of wound healing by reducing neutrophil infiltration.
METHODS AND RESULTS: Transcriptome analysis of Ly6Clo macrophages and Ly6Chigh M1-like macrophages (Ly6Chi macrophages) harvested from the infarcted heart revealed that Ly6Clo macrophages highly expressed matrix metalloproteinase (MMP)-12 mRNA compared to Ly6Chi macrophages. MMP-12 expression was enhanced in the infarcted heart and preferentially observed in Ly6Clo 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 Ly6Clo macrophages improves the survival after MI possibly through the promotion of wound healing by reducing neutrophil infiltration.