Department of Cardiology, Renmin Hospital of Wuhan University, Department of Geriatrics, Zhongnan Hospital of Wuhan University, Wuhan University, 238 Jiefang Road, Wuhan, 430060, China.
Department of Cardiology, Renmin Hospital of Wuhan University, Hubei Key Laboratory of Cardiology, Cardiovascular Research Institute, Wuhan University, Wuhan, China.
Cell Mol Life Sci. 2023 Oct 12;80(11):324. doi: 10.1007/s00018-023-04974-7.
Immune response plays a crucial role in post-myocardial infarction (MI) myocardial remodeling. Neogenin (Neo1), a multifunctional transmembrane receptor, plays a critical role in the immune response; however, whether Neo1 participates in pathological myocardial remodeling after MI is unclear. Our study found that Neo1 expression changed significantly after MI in vivo and after LPS + IFN-γ stimulation in bone marrow-derived macrophages (BMDMs) in vitro. Neo1 functional deficiency (using a neutralizing antibody) and macrophage-specific Neo1 deficiency (induced by Neo1;Cx3cr1 mice) increased infarction size, enhanced cardiac fibrosis and cardiomyocyte apoptosis, and exacerbated left ventricular dysfunction post-MI in mice. Mechanistically, Neo1 deficiency promoted macrophage infiltration into the ischemic myocardium and transformation to a proinflammatory phenotype, subsequently exacerbating the inflammatory response and impairing inflammation resolution post-MI. Neo1 deficiency regulated macrophage phenotype and function, possibly through the JAK1-STAT1 pathway, as confirmed in BMDMs in vitro. Blocking the JAK1-STAT1 pathway with fludarabine phosphate abolished the impact of Neo1 on macrophage phenotype and function, inflammatory response, inflammation resolution, cardiomyocyte apoptosis, cardiac fibrosis, infarction size and cardiac function. In conclusion, Neo1 deficiency aggravates inflammation and left ventricular remodeling post-MI by modulating macrophage phenotypes and functions via the JAK1-STAT1 signaling pathway. These findings highlight the anti-inflammatory potential of Neo1, offering new perspectives for therapeutic targets in MI treatment. Neo1 deficiency aggravated inflammation and left ventricular remodeling after MI by modulating macrophage phenotypes and functions via the JAK1-STAT1 signaling pathway.
免疫反应在心肌梗死后（MI）心肌重构中起着至关重要的作用。Neogenin（Neo1）是一种多功能跨膜受体，在免疫反应中起着关键作用；然而，Neo1 是否参与 MI 后的病理性心肌重构尚不清楚。我们的研究发现，Neo1 表达在体内 MI 后和体外骨髓来源的巨噬细胞（BMDM）中 LPS+IFN-γ刺激后发生明显变化。Neo1 功能缺失（使用中和抗体）和巨噬细胞特异性 Neo1 缺失（通过 Neo1;Cx3cr1 小鼠诱导）增加了 MI 后小鼠的梗死面积，增强了心脏纤维化和心肌细胞凋亡，并加重了左心室功能障碍。在机制上，Neo1 缺失促进了巨噬细胞浸润缺血性心肌并向促炎表型转化，随后加剧了 MI 后的炎症反应并损害了炎症的消退。Neo1 缺失调节巨噬细胞表型和功能，可能通过 JAK1-STAT1 通路，这在体外 BMDM 中得到了证实。用氟达拉滨磷酸盐阻断 JAK1-STAT1 通路消除了 Neo1 对巨噬细胞表型和功能、炎症反应、炎症消退、心肌细胞凋亡、心脏纤维化、梗死面积和心功能的影响。总之，Neo1 通过调节 JAK1-STAT1 信号通路改变巨噬细胞表型和功能，加重 MI 后炎症和左心室重构。这些发现强调了 Neo1 的抗炎潜力，为 MI 治疗的治疗靶点提供了新的视角。
