Myeloid interleukin-4 receptor a is essential in postmyocardial infarction healing by regulating inflammation and fibrotic remodeling

Interleukin-4 receptor a (IL4Ra) signaling plays an important role in cardiac remodeling during myocardial infarction (MI). However, the target cell type(s) of IL4Ra signaling during this remodeling remains unclear. Here, we investigated the contribution of endogenous myeloid-specific IL4Ra signaling in cardiac remodeling post-MI. We established a murine myeloid-specific IL4Ra knockout (MyIL4RaKO) model with LysM promoter-driven Cre recombination. Macrophages from MyIL4RaKO mice showed significant downregulation of alternatively activated macrophage markers but an upregulation of classical activated macrophage markers both in vitro and in vivo, indicating the successful inactivation of IL4Ra signaling in macrophages. To examine the role of myeloid IL4Ra during MI, we subjected MyIL4RaKO and littermate floxed control (FC) mice to MI. We found that cardiac function was significantly impaired as a result of myeloid-specific IL4Ra deficiency. This deficiency resulted in a dysregulated inflammatory response consisting of decreased production of anti-inflammatory cytokines. Myeloid IL4Ra deficiency also led to reduced collagen 1 deposition and an imbalance of matrix metalloproteinases (MMPs)/tissue inhibitors of metalloproteinases (TIMPs), with upregulated MMPs and downregulated TIMPs, which resulted in insufficient fibrotic remodeling. In conclusion, this study identifies that myeloid-specific IL4Ra signaling regulates inflammation and fibrotic remodeling during MI. Therefore, myeloid- specific activation of IL4Ra signaling could offer protective benefits after MI.