EGF-like repeats and discoidin I-like domain 3 (EDIL3) deficiency improves post-myocardial infarction healing via neutrophil extracellular traps (NETs) mediated pro-inflammatory macrophage polarization

Abstract

Abstract After myocardial infarction (MI), injured cardiomyocytes recruit neutrophils, leading to extravasated monocytes polarized to inflammatory and reparative macrophages sequentially, which contribute to the healing and regenerative process. As an endogenous leukocyte-endothelial adhesion inhibitor, the role of EDIL3 in MI remains obscure. We found that serum EDIL3 level of MI patients was negatively associated with MI biomarkers, including CK-MB, cTnI and MGB. EDIL3−/− mice showed improved infarct healing with lower mortality, better cardiac function and decreased infarcted size compared with wild type (WT). Enhanced neutrophil infiltration resulted in the increase of Ly6Chi MHClo Mertk− macrophages, which we identified to be pro-inflammatory, protecting EDIL3−/− mice hearts from excessive fibrosis. A neutrophil infiltration antagonist not only eliminated the difference in cardiac function between WT and EDIL3−/− mice, but also reduced Ly6Chi MHClo Mertk− macrophage polarization. These data implied that improved cardiac healing was associated with increased infiltration of neutrophil and it mediated macrophage polarization. Notably, we confirmed that this polarization depended on NETs, which were more abundant in hearts and serum in EDIL3−/− mice than in WT. Indeed, self-DNA released from NETs primed the pro-inflammatory polarization of macrophages. The degradation of NETs by DNase I reduced this polarization and thus affected post-MI outcome, indicating the pivotal role of NETs in MI healing. Meanwhile, the pro-inflammatory macrophages induced apoptosis of neutrophils and restrained excessive inflammation. Our findings reveal a novel neutrophil–macrophage crosstalk essential to cardiac healing after MI.