Inactivation of Interleukin-4 Receptor α Signaling in Myeloid Cells Protects Mice From Angiotensin II/High Salt-Induced Cardiovascular Dysfunction Through Suppression of Fibrotic Remodeling.
Inactivation of Interleukin-4 Receptor α Signaling in Myeloid Cells Protects Mice From Angiotensin II/High Salt-Induced Cardiovascular Dysfunction Through Suppression of Fibrotic Remodeling.
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DOI：
10.1161/jaha.120.017329
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发表时间：
2021-07-06
影响因子：
5.4
通讯作者：
Mortensen RM
中科院分区：
文献类型：
--
作者：
Song J;Frieler RA;Vigil TM;Ma J;Brombacher F;Goonewardena SN;Goldstein DR;Mortensen RM
高血压引起的心血管重塑的特点是慢性低度炎症。白介素-4 受体 α (IL-4Rα) 信号传导在心血管重塑中发挥重要作用，但靶细胞类型尚不清楚。在这里，我们研究了骨髓特异性 IL-4Rα 信号在血管紧张素 II 和高盐诱导的心血管重塑中的作用。髓样 IL-4Rα 缺陷抑制了替代激活的巨噬细胞标记物的体外和体内表达，包括 Arg1（精氨酸酶 1）、Ym1（几丁质酶 3 样 3）和 Relmα/Fizz1（抵抗素样分子 α）。血管紧张素 II 和高盐治疗后，骨髓特异性 IL-4Rα 缺乏并没有改变心脏和主动脉内的肥厚性重塑。然而，髓系 IL-4Rα 缺陷通过抑制促纤维化途径和增强抗纤维化信号传导，导致纤维化大幅减少。 MyIL4RαKO 小鼠中纤维化的减少与心肌功能的显着保存相关，并且是由替代性巨噬细胞活化减弱介导的。髓样 IL-4Rα 信号传导通过控制替代性巨噬细胞激活和调节纤维化相关信号传导，在很大程度上参与纤维化心血管重塑。抑制骨髓 IL-4Rα 信号传导可能是预防高血压心血管疾病的潜在策略。
Hypertension‐induced cardiovascular remodeling is characterized by chronic low‐grade inflammation. Interleukin‐4 receptor α (IL‐4Rα) signaling is importantly involved in cardiovascular remodeling, however, the target cell type(s) is unclear. Here, we investigated the role of myeloid‐specific IL‐4Rα signaling in cardiovascular remodeling induced by angiotensin II and high salt. Myeloid IL‐4Rα deficiency suppressed both the in vitro and in vivo expression of alternatively activated macrophage markers including Arg1 (arginase 1), Ym1 (chitinase 3‐like 3), and Relmα/Fizz1 (resistin‐like molecule α). After angiotensin II and high salt treatment, myeloid‐specific IL‐4Rα deficiency did not change hypertrophic remodeling within the heart and aorta. However, myeloid IL‐4Rα deficiency resulted in a substantial reduction in fibrosis through the suppression of profibrotic pathways and the enhancement of antifibrotic signaling. Decreased fibrosis was associated with significant preservation of myocardial function in MyIL4RαKO mice and was mediated by attenuated alternative macrophage activation. Myeloid IL‐4Rα signaling is substantially involved in fibrotic cardiovascular remodeling by controlling alternative macrophage activation and regulating fibrosis‐related signaling. Inhibiting myeloid IL‐4Rα signaling may be a potential strategy to prevent hypertensive cardiovascular diseases.