Abstract
Background: Myelomonocytic cells are involved in both the initial injury phase and the healing process of myocardial infarction (MI). However, the exact interaction of inflammatory myeloid cells and prominent cytokines remains only partly understood. Objective: The goal of the study was to investigate the either cardioprotective or in part adverse role of lysozyme M positive (LysM+) and granulocyte-receptor 1 positive (Gr-1+) immune cells on cardiac injury and healing in a murine model of MI. Methods and results: MI was induced in 8 to 12 week-old male mice (C57BL/6 background) by ligation of the left anterior descending (LAD) coronary artery. Compared to LysMCre controls, LysM+ cell depleted LysMiDTR transgenic mice (depletion 3d prior MI by diphtheria toxin application, 25 ng/g body weight) showed a decreased influx of CD45.2+/CD3-/CD11b+/Gr-1high neutrophils into infarcted myocardium 1d post MI (measured by flow cytometric analysis). Additionally cardiac mRNA expression levels of inflammatory cytokines like INFγ and TNFα were decreased 7d post MI. To more specifically assess the role of neutrophils, we depleted C57BL/6 mice with a monoclonal anti-Gr-1 antibody and found increased mortality early after MI as well as a decrease in INFγ mRNA expression 1d and 7d post MI. MCP-1 (CCL2) and CCR2 mRNA were reduced 3d after MI according to decreased amount of CD11b+/Ly6G-/Ly6Chigh inflammatory monocytes in the infarcted myocardium of anti-Gr-1 treated mice. LAD ligated INFγ-/- mice displayed a significantly reduced survival, worsening of left ventricular function and an impaired inflammatory cell infiltration compared to C57BL/6 controls. Conclusion: We provide evidence that neutrophils and INFγ play an essential role in survival and cardiac remodeling following MI. Our data indicate that neutrophils are required for monocyte chemotaxis. We conclude, that strategies to combat the inflammatory injury in MI must consider a potentially beneficial effect of early neutrophil influx into infarcted myocardium.
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