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

Interleukin-4 receptor alpha (IL4R alpha) signaling plays an important role in cardiac remodeling during myocardial infarction (MI). However, the target cell type(s) of IL4R alpha signaling during this remodeling remains unclear. Here, we investigated the contribution of endogenous myeloid-specific IL4R alpha signaling in cardiac remodeling post-MI. We established a murine myeloid-specific IL4R alpha knockout (MyIL4R alpha KO) model with LysM promoter-driven Cre recombination. Macrophages from MyIL4R alpha KO 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 IL4R alpha signaling in macrophages. To examine the role of myeloid IL4R alpha during MI, we subjected MyIL4R alpha KO and littermate floxed control (FC) mice to MI. We found that cardiac function was significantly impaired as a result of myeloid-specific IL4R alpha deficiency. This deficiency resulted in a dysregulated inflammatory response consisting of decreased production of anti-inflammatory cytokines. Myeloid IL4R alpha 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 IL4R alpha signaling regulates inflammation and fibrotic remodeling during MI. Therefore, myeloid-specific activation of IL4R alpha signaling could offer protective benefits after MI. NEW & NOTEWORTHY This study showed, for the first time, the role of endogenous IL4R alpha signaling in myeloid cells during cardiac remodeling and the underlying mechanisms. We identified myeloid cells are the critical target cell types of IL4R alpha signaling during cardiac remodeling post-MI. Deficiency of myeloid IL4R alpha signaling causes deteriorated cardiac function post-MI, due to dysregulated inflammation and insufficient fibrotic remodeling. This study sheds light on the potential of activating myeloid-specific IL4R alpha signaling to modify remodeling post-MI. This brings hope to patients with MI and diminishes side effects by cell typespecific instead of whole body treatment.

Automated summary

This study revealed the crucial role of myeloid IL4R alpha signaling in cardiac remodeling post-MI, showing that myeloid cells are the main target cell types of this signaling. Deficiency of myeloid IL4R alpha signaling resulted in impaired cardiac function post-MI due to dysregulated inflammation and insufficient fibrotic remodeling. These findings highlight the potential of activating myeloid-specific IL4R alpha signaling to improve remodeling post-MI, offering hope to MI patients and reducing side effects compared to whole body treatment.