A sequential interferon gamma directed chemotactic cellular immune response determines survival and cardiac function post myocardial infarction

Aims: Myelomonocytic cells are critical in injury and healing post myocardial infarction (MI). Mechanisms of regulation, however, are incompletely understood. The aim of the study was to elucidate the role of interferon gamma (IFN-γ) in the orchestrated inflammatory response in a murine model of MI. Methods and results: MI was induced in 8 to 12 week-old male mice (C57BL/6 background) by permanent ligation of the left anterior descending coronary artery (LAD). Lysozyme M (LysM)+ cell depleted LysMiDTR transgenic mice displayed a reduced influx of CD45.2+/CD3-/CD11b+/Gr-1high neutrophils into infarcted myocardium 1d post MI compared to infarcted controls, paralleled by decreased cardiac mRNA levels of IFN-γ and tumor necrosis factor alpha (TNF-α). Mortality after MI was significantly increased in LysM+ cell-depleted mice within 28d post MI. To more specifically address the role of neutrophils, we depleted C57BL/6 mice with a monoclonal anti-Gr-1 antibody and found increased mortality, deteriorated cardiac function as well as decreased cardiac IFN-γ mRNA expression early after MI. Ccl2, Cxcl1, Cx3cl1 and Il12b mRNA were reduced 3d after MI, as was the amount of CD11b+/Ly6G-/Ly6Chigh inflammatory monocytes. LAD-ligated Cramp-/- mice lacking cathelicidin important in neutrophil-dependent monocyte chemotaxis as well as IFNγ-/- and TNFα-/- mice phenocopied Gr-1+ cell-depleted mice, supporting a regulatory role of IFN-γ impacting on both the sequence of inflammatory cell invasion and cardiac outcome early after MI. The use of conditional IFN-γ receptor deficient mice indicated a direct effect of IFN-γ on LysM+ cells in cardiac injury post MI. Using IFN-γ reporter mice and flow cytometry, we identified cardiac lymphoid cells (CD4+ and CD8+ T cells and natural killer cells) as primary source of this cytokine in the cardiac inflammatory response post MI. Conclusion: IFN-γ directs a sequential chemotactic cellular immune response and determines survival and cardiac function post MI.