Abstract
BackgroundLeft 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 ResultsWe 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. M1 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.ConclusionsThe IL-23/IL-17A immune axis and γδT cells are potentially promising therapeutic targets after MI to prevent progression to end-stage dilated cardiomyopathy.
Highlights
We investigated whether IL-23 acts as an upstream regulator of IL-17A in infarcted heart
Two recent articles demonstrated that IL-17A is involved in the early cardiomyocyte death evident in ischemia–reperfusion injury, with functional involvement demonstrated 2 to 3 hours after reperfusion.[22,23]
Despite the finding that infarct size 24 hours after surgery was comparable among all mice including WT, ablation of IL-23, IL-17A, or CD4À TCRcd+ (cdT) cells improved survival after 7 days, limited infarct expansion, and reduced fibrosis in the noninfarcted myocardium, alleviating Left ventricular (LV) dilatation and systolic dysfunction on day 28 post-myocardial infarction (MI)
Summary
The leukocyte-enriched fraction was collected from sham-operated and infarcted hearts on day 6 post-MI, and cells were cultured with either vehicle or IL-23 (10 ng/mL) for 24 hours (Figure 2). Intracellular cytokine staining revealed that 90.1±1.2% of IL17A-expressing cells in the infarcted hearts on day 7 post-MI were CD3+ T lymphocytes (Figure 5B).
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