Deficiency in IL-23, IL-17A, or γδT cells improved survival after 7 days and alleviated left ventricular dilatation and systolic dysfunction on day 28 post-myocardial infarction.
Does deficiency in the IL-23/IL-17A axis or γδT cells improve survival and prevent LV remodeling after myocardial infarction in mice?
The IL-23/IL-17A immune axis and γδT cells drive late-stage LV remodeling and dysfunction after MI, identifying them as potential therapeutic targets to prevent progression to heart failure.
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 γδT 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 γδT 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 CD4(-) TCRγδ(+) (γδT) cells. Toll-like receptor signaling and IL-1β worked in concert with IL-23 to drive expansion and IL-17A production in cardiac γδT cells, whereas the sphingosine-1-phosphate receptor and CCL20/CCR6 signaling pathways mediated γδT 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 γδT cells are potentially promising therapeutic targets after MI to prevent progression to end-stage dilated cardiomyopathy.
Yan et al. (Wed,) conducted a other in Myocardial Infarction. Deficiency in IL-23, IL-17A, or γδT cells vs. Wild-type mice was evaluated on Survival, infarct expansion, fibrosis, LV dilatation, and systolic dysfunction. Deficiency in IL-23, IL-17A, or γδT cells improved survival after 7 days and alleviated left ventricular dilatation and systolic dysfunction on day 28 post-myocardial infarction.