Abstract 14348: Deleterious Effect of IL-23/IL-17A Axis and γδT Cells in Left Ventricular Remodeling after Myocardial Infarction in Rodent
Abstract 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. IL-23 and IL-17A-producing cells are involved in the pathogenesis of various inflammatory diseases. We examine the impact of these cytokines on post-MI cardiac remodeling. Methods and results: We created a large size of myocardial infarction by permanent ligation of coronary artery and identified a potential link between IL-23-IL-17A axis and γδT cells on late-stage left ventricular remodeling after MI. Despite the fact that infarct size at 24 hours after surgery was similar to wild-type mice, ablation of IL-23, IL-17, and γδT cells improved survival after 7 days, limiting infarct expansion and fibrosis in non-infarct myocardium, alleviating LV dilatation and systolic dysfunction on day 28 post-MI. M1 macrophages and neutrophils were the major cellular source of IL-23, whereas γδT cells were the major cellular source of IL-17A in infarcted heart. Toll-like receptor signaling and IL-1β work concert with IL-23 to drive expansion and IL-17A production of cardiac γδT cells, whereas sphingosine-1-phosphate receptor and CCL20/CCR6 signaling pathways mediate γδT cell recruitment into the infarcted heart. IL-17A was not involved in the acute inflammatory response, but specifically functioned in late remodeling stages by promoting sustained infiltration of neutrophils and macrophages, stimulating macrophages to produce pro-inflammatory cytokines, aggravating cardiomyocyte death, enhancing fibroblast proliferation and pro-fibrotic gene expression.
Conclusion: This study indicated that the late remodeling stage-specific effect of IL-17A is a potential therapeutic target for preventing the development of chronic heart failure due to post-MI cardiac remodeling.
- © 2012 by American Heart Association, Inc.