Abstract P3075: Neutrophil Secreted Chitinase 3-like-1 Antagonizes Macrophage Reparative Polarization And Contributes To Ventricular Dysfunction After Myocardial Infarction

Abstract

Clinical studies show that chitinase 3-like-1 (CHI3L1) is a biomarker and predictor of all-cause mortality in heart failure. Studies from our lab demonstrated that CHI3L1 is elevated in hearts post-MI, and CHI3L1 deficiency in mice results in preserved ventricular structure and function post-MI. Furthermore, we found that CHI3L1 is secreted from activated neutrophils but has no effect on neutrophil recruitment in hearts after MI. The goal of the current study was to elucidate mechanisms whereby CHI3L1 contributes to exacerbated cardiac dysfunction after MI. Post-MI neutrophil recruitment is followed by the sequential programming of macrophages to pro-inflammatory or pro-reparative phenotypes. We sought to determine the impact of neutrophil-secreted CHI3L1 on macrophage polarization. Activated neutrophils isolated from Chil1 +/+ and Chil1 -/- mice were co-cultured with bone marrow-derived macrophages. We found that macrophages directly co-cultured with Chil1 -/- but not Chil1 +/+ neutrophils showed upregulation of the pro-reparative markers, Chil4 and Arg1 (n=5/group, p<0.05). Additionally, direct co-culture of Chil1 -/- neutrophils and macrophages showed trends towards downregulation of the pro-inflammatory polarization markers, Il1b and Tnfa relative to macrophages co-cultured with Chil +/+ neutrophils. These data suggest that neutrophil-derived CHI3L1 may antagonize signaling to polarize macrophages towards a pro-reparative phenotype that may explain delayed scar formation and exacerbated ventricular dysfunction after MI. Future efforts will elucidate the signaling role of CHI3L1 associated with neutrophil extracellular traps (NETs) on macrophage function.