Eosinophils Mediate Alternative Activation of Macrophages via IL-4 in the Infarcted Adult Mouse Heart to Prevent Adverse Cardiac Remodelling

Introduction: Alternative activation of macrophages by IL-4 promotes tissue repair. We have observed that peripheral blood eosinophil count declines in patients following the onset of myocardial infarction (MI) symptoms. Eosinophils contain preformed IL-4 within their cytoplasmic granules but it is not known whether they are recruited to the infarct zone or have a role in infarct repair. Hypothesis: Eosinophils are recruited to the infarct zone post-MI where they supply IL-4 to promote alternative activation of macrophages and limit adverse cardiac remodelling. Methods: MI was induced by permanent coronary artery ligation (CAL) in 12-15 week-old male ΔdblGATA mice deficient in eosinophils, or wild-type (WT) Balb/c and C57Bl/6 mice. Cardiac function was assessed 7 days after CAL by high-resolution ultrasound and flow cytometry was performed on single cell digests of infarct zone tissue. Results: The number of CD11b + F4/80 - Siglec-F + eosinophils in the infarct zone of WT mice increased in the days following infarction. Eosinophil-deficient ΔdblGATA mice had greater left ventricular dilation relative to WT mice (end-systolic area: 29±2 cm 2 vs. 22±2 cm 2 ; p=0.02) and worse cardiac function (ejection fraction: 22±4% vs. 34±4%; p=0.04, n=8-9 per group) at day 7 post-MI. This outcome was reproduced in C57Bl/6 mice following pharmacological eosinophil depletion with Siglec-F anti-serum. Expression of CD206, a marker for alternatively activated macrophages, was reduced on infarct zone CD11b + F4/80 + Ly6G - macrophages from ΔdblGATA mice, but was restored by intra-peritoneal eosinophil replenishment. IL-4 complex (5μg IL-4, i.p.) given 24 hours post-MI had no effect on cardiac function post-MI in WT Balb/c mice, but rescued structural and functional deterioration in ΔdblGATA mice (end-systolic area: 23±1 vs. 29±1 cm 2 ; p=0.02 and ejection fraction: 32±2% vs. 23±2% in IL-4 and PBS treated ΔdblGATA mice respectively, p=0.02, n=8-15 per group). Conclusions: This study provides the first evidence for recruitment of eosinophils to the heart following MI and shows that they are required for alternative activation of infarct zone macrophages and prevention of adverse cardiac remodelling through provision of IL-4 during infarct repair.