Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan.
Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan.
Am J Physiol Heart Circ Physiol. 2021 Jan 1;320(1):H323-H337. doi: 10.1152/ajpheart.00251.2020. Epub 2020 Nov 8.
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. 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.
白细胞介素 4 受体 α（IL4Rα）信号在心肌梗死后（MI）的心脏重构中起着重要作用。然而，在这种重构过程中，IL4Rα 信号的靶细胞类型仍不清楚。在这里，我们研究了内源性髓系特异性 IL4Rα 信号在 MI 后心脏重构中的作用。我们利用 LysM 启动子驱动的 Cre 重组建立了一种鼠源髓系特异性 IL4Rα 敲除（MyIL4RαKO）模型。MyIL4RαKO 小鼠的巨噬细胞在体外和体内均表现出交替激活的巨噬细胞标志物的显著下调，但经典激活的巨噬细胞标志物的上调，表明巨噬细胞中 IL4Rα 信号的成功失活。为了研究髓系 IL4Rα 在 MI 中的作用，我们使 MyIL4RαKO 和同窝 floxed 对照（FC）小鼠发生 MI。我们发现，由于髓系特异性 IL4Rα 缺乏，心脏功能显著受损。这种缺乏导致炎症反应失调，包括抗炎细胞因子产生减少。髓系 IL4Rα 缺乏也导致胶原 1 沉积减少和基质金属蛋白酶（MMPs）/金属蛋白酶组织抑制剂（TIMPs）的失衡，MMPs 上调，TIMP 下调，导致纤维化重塑不足。总之，这项研究表明，髓系特异性 IL4Rα 信号调节 MI 期间的炎症和纤维化重塑。因此，MI 后髓系特异性激活 IL4Rα 信号可能提供保护益处。这项研究首次表明，内源性 IL4Rα 信号在心肌梗死后的心肌重构过程中调节骨髓细胞，并阐明了潜在的机制。我们确定骨髓细胞是 MI 后心脏重构过程中 IL4Rα 信号的关键靶细胞类型。髓系 IL4Rα 信号缺失导致 MI 后心脏功能恶化，原因是炎症失调和纤维化重塑不足。这项研究揭示了激活髓系特异性 IL4Rα 信号以改变 MI 后重塑的潜力。这为 MI 患者带来了希望，并通过细胞类型特异性而非全身治疗来减少副作用。
