Abstract 336: Interleukin 4 and 13 Signaling in Myeloid Cells Regulates Cardiac Regeneration

Introduction: Heart failure is a very important disease in the United States and worldwide, with a projected prevalence of 8 million by 2030. Current therapy partially decreases progression; however, mortality continues to be high, and progression to terminal HF is still significant, requiring heart transplant and other interventions that further increase morbidity and overall disease burden and costs. Therefore, the need to develop new therapies that target HF progression. Our prior work and published studies demonstrate that IL13 promotes cardiac regeneration, however, the mechanism mediating this response is currently unknown. IL13 and IL4 share a common receptor, and both cytokines are known to polarize macrophages into a pro-reparative phenotype. Here, we hypothesize that IL4/13 signaling in myeloid cells promotes heart regeneration after cardiac injury. Methods and Results: We compared cardiac regeneration in IL4Ra null/FLOXed (IL4Rα-/fl) and IL4Rα-/fl lysosome M Cre littermate mice, knocking out IL4Rα in myeloid cells. We performed apical resection on postnatal day 1 (P1) mice and assessed cardiac regeneration by histological analysis. We found that mice lacking IL4Ra in myeloid cells (IL4rafl/-, LysMCre) had significantly impaired cardiac regenerative capacity compared to Cre negative littermate controls. We also performed gene expression analysis by qPCR in whole hearts collected at 2dpi to quantify macrophages markers. Cre positive mice trended higher for expression of arginase 1 and mannose receptor 1 (p=0.055 and 0.057, respectively; student t-test) compared to Cre negative littermates. Conclusions and Discussion: Lack of IL4/13 signaling in myeloid cells impairs cardiac regeneration after injury in neonatal mice and modulated expression of immune markers. To confirm these results, flow cytometry to quantify immune cell infiltration can be performed. Other components that limit damage extension can also be assessed, like angiogenesis and cardiomyocyte proliferation. Our data suggest that IL4/IL13 signaling polarizes myeloid cells to a pro-reparative state in the neonatal heart. Additional studies are required to delineate the specific cell population mediating this response.