ajpheart.2020.pdf

 

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