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Myeloid interleukin-4 receptor α (IL4Rα) is essential in post-myocardial infarction healing by regulating inflammation and fibrotic remodeling

Song, J.
Frieler, R.A.
Whitesall, S.E.
Chung, Y.
Vigil, T.M.
Muir, L.A.
Ma, J.
Brombacher, F.
Goonewardena, S.N.
Lumeng, C.N.
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Interleukin-4 receptor α (IL4Rα) signaling plays an important role in cardiac remodeling during myocardial infarction (MI). However, the target cell type(s) of IL4Rα signaling during this remodeling remains unclear. Here, we investigated the contribution of endogenous myeloid-specific IL4Rα signaling in cardiac remodeling post-MI. We established a murine myeloid-specific IL4Rα knockout (MyIL4RαKO) model with LysM promoter-driven Cre recombination. Macrophages from MyIL4RαKO 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 IL4Rα signaling in macrophages. To examine the role of myeloid IL4Rα during MI, we subjected MyIL4RαKO and littermate floxed control (FC) mice to MI. We found that cardiac function was significantly impaired as a result of myeloid-specific IL4Rα deficiency. This deficiency resulted in a dysregulated inflammatory response consisting of decreased production of anti-inflammatory cytokines. Myeloid IL4Rα 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 IL4Rα signaling regulates inflammation and fibrotic remodeling during MI. Therefore, myeloid-specific activation of IL4Rα signaling could offer protective benefits after MI.NEW & NOTEWORTHY This study showed, for the first time, the role of endogenous IL4Rα signaling in myeloid cells during cardiac remodeling and the underlying mechanisms. We identified myeloid cells are the critical target cell types of IL4Rα signaling during cardiac remodeling post-MI. Deficiency of myeloid IL4Rα 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 IL4Rα signaling to modify remodeling post-MI. This brings hope to patients with MI and diminishes side effects by cell type-specific instead of whole body treatment.
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American Physiological Society
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IL4Rα,myocardial infarction,Fibrosis,Cardiac remodeling,Macrophage
Song J, Frieler RA, Whitesall SE, Chung Y, Vigil TM, Muir LA, Ma J, Brombacher F, Goonewardena SN, Lumeng CN, Goldstein DR, Mortensen RM. Myeloid interleukin-4 receptor α is essential in postmyocardial infarction healing by regulating inflammation and fibrotic remodeling. Am J Physiol Heart Circ Physiol. 2021 Jan 1;320(1):H323-H337. doi: 10.1152/ajpheart.00251.2020. Epub 2020 Nov 8.
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