Abstract GS.09: Interleukin 13 Signaling To Macrophages Promotes Recovery After Myocardial Infarction In Mice

Abstract

Introduction: There is great interest in identifying signaling pathways that promote pro-reparative macrophage phenotypes in the heart. Considering the remarkable cardiac healing potential of neonatal mice, we employ this model to identify pro-reparative mechanisms that can be applied to promote cardiac repair in adults after myocardial infarction (MI). We show that IL13/IL4Rα signaling specifically on macrophages mediates neonatal heart regeneration and activation of this pathway in adult mice promotes cardiac functional recovery in post-MI. Results: We developed IL4Rα fl/fl ;CX3CR1 Cre mice (IL4Rα MacKO ) to delete IL4Rα specifically in macrophages. Neonatal IL4Rα MacKO and control mice were subjected to MI on postnatal day 1 (P1). Following injury, IL4Rα MacKO mice had significantly larger scars at 8 days post injury (dpi) and lower ejection fraction and capillary density at 21 dpi. Thus, macrophage IL4Rα expression is critical for cardiac functional recovery following injury in neonates. Using fluorescent reporter mice, we found that IL13, a ligand for IL4Rα, is produced almost exclusively by type 2 innate lymphoid cells in the neonatal heart. Interestingly, we didn’t find any cellular source of IL13 in the adult mouse heart. Considering the decline in cardiac production of IL13 from neonatal to adult stages, we postulated that reactivation of IL4Rα in the adult heart would improve cardiac healing post MI in adults. Indeed, daily IL13 administration significantly improved cardiac function post MI in adult mice, and this improvement was mediated entirely by IL4Rα expression on macrophages as IL4Rα MacKO mice showed no functional improvement with IL13 administration. Intriguingly, while IL13 administration to control mice improved cardiac function, administration to IL4Rα MacKO mice further exacerbated post MI mortality and scar size compared to animals receiving PBS, suggesting multiple cardiac cell types respond to IL13 resulting in beneficial or detrimental outcomes. Conclusions: Our data elucidates a strongly pro-reparative role for IL13 signaling directly to macrophages. While this signaling pathway is active in neonatal stages, we demonstrate that re-activation by IL13 administration is required to promote cardiac repair in adults.