Deleterious Effect of the IL ‐23/ IL ‐17 A Axis and γδ T Cells on Left Ventricular Remodeling After Myocardial Infarction

Background Left ventricular ( LV ) remodeling leads to chronic heart failure and is a main determinant of morbidity and mortality after myocardial infarction ( MI ). At the present time, therapeutic options to prevent LV remodeling are limited. Methods and Results We created a large MI by permanent ligation of the coronary artery and identified a potential link between the interleukin ( IL )–23/ IL ‐17A axis and γδ T cells that affects late‐stage LV remodeling after MI . Despite the finsinf that infarct size 24 hours after surgery was similar to that in wild‐type mice, a deficiency in IL ‐23, IL ‐17A, or γδ T cells improved survival after 7 days, limiting infarct expansion and fibrosis in noninfarcted myocardium and alleviating LV dilatation and systolic dysfunction on day 28 post‐ MI . M 1 macrophages and neutrophils were the major cellular source of IL ‐23, whereas >90% of IL ‐17A‐producing T cells in infarcted heart were CD 4 − TCR γδ + (γδ T ) cells. Toll‐like receptor signaling and IL ‐1β worked in concert with IL ‐23 to drive expansion and IL ‐17A production in cardiac γδ T cells, whereas the sphingosine‐1‐phosphate receptor and CCL 20/ CCR 6 signaling pathways mediated γδ T cell recruitment into infarcted heart. IL ‐17A was not involved in the acute inflammatory response, but it functioned specifically in the late remodeling stages by promoting sustained infiltration of neutrophils and macrophages, stimulating macrophages to produce proinflammatory cytokines, aggravating cardiomyocyte death, and enhancing fibroblast proliferation and profibrotic gene expression. Conclusions The IL ‐23/ IL ‐17A immune axis and γδ T cells are potentially promising therapeutic targets after MI to prevent progression to end‐stage dilated cardiomyopathy.