Optogenetic vagal nerve stimulation attenuates heart failure by limiting the generation f monocyte-derived inflammatory CCRL2+ macrophages

IF 25.5 1区医学 Q1 IMMUNOLOGY

Immunity Pub Date : 2025-06-27 DOI:10.1016/j.immuni.2025.06.003

Guoqi Li, Congcong Zhang, Yang Li, Jie Yang, Jianing Wu, Yihui Shao, Ke Ma, Xinyu Zhang, Shuolin Zhu, Jie Du, Xin-Liang Ma, Liping Wang, Zhuofeng Lin, Ping Li, Yulin Li

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引用次数: 0

Abstract

Parasympathetic neuronal dysfunction is associated with heart failure (HF), yet the underlying mechanism is poorly understood. Here, we report that targeted vagal nerve stimulation (VNS) using optogenetics attenuated cardiac remodeling and HF induced by pressure overload. Unbiased approaches revealed that VNS decreased the proportion of Ccrl2⁺ macrophages, which were derived from myeloid monocytes and exhibited a distinct tumor necrosis factor alpha (TNF-α) cytokine-responsive, pro-hypertrophic, and profibrotic signature. Elimination of Ccrl2⁺ macrophages prevented cardiac remodeling and HF. Ccrl2⁺-macrophage-specific overexpression or global genetic loss of α7 nicotinic acetylcholine receptor (α7nAChR) highlighted their crucial contribution to VNS-mediated cardioprotection. Activation of α7nAChR inhibited Ccrl2⁺ macrophages’ TNF-α responsiveness through increased expression of the transcription factor NRF2. Cardiac Ccrl2⁺ macrophages and TNF-α-responsive proteins positively correlated with cardiac remodeling and dysfunction in humans. An α7nAChR agonist effectively blocked the development of HF. These results suggest that the vagal neuroimmune axis modulates HF and is a promising target for treatment.

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光遗传迷走神经刺激通过限制单核细胞来源的炎性CCRL2+巨噬细胞的产生来减轻心力衰竭

副交感神经功能障碍与心力衰竭（HF）有关，但其潜在机制尚不清楚。在这里，我们报道了利用光遗传学靶向迷走神经刺激（VNS）减轻压力过载引起的心脏重塑和HF。无偏倚方法显示，VNS降低了来自髓系单核细胞的Ccrl2+巨噬细胞的比例，并表现出明显的肿瘤坏死因子α (TNF-α)细胞因子反应，促肥大和促纤维化特征。消除Ccrl2+巨噬细胞可预防心脏重构和HF。α7烟碱乙酰胆碱受体（α7nAChR）的Ccrl2+-巨噬细胞特异性过表达或全局遗传缺失突出了它们在vns介导的心脏保护中的重要作用。α7nAChR的激活通过增加转录因子NRF2的表达抑制Ccrl2+巨噬细胞对TNF-α的反应性。心脏Ccrl2+巨噬细胞和TNF-α-反应蛋白与人类心脏重构和功能障碍呈正相关。α7nAChR激动剂可有效阻断HF的发展。这些结果表明迷走神经免疫轴调节心衰，是一个有希望的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Immunity 医学-免疫学

CiteScore

49.40

自引率

2.20%

发文量

205

审稿时长

6 months

期刊介绍： Immunity is a publication that focuses on publishing significant advancements in research related to immunology. We encourage the submission of studies that offer groundbreaking immunological discoveries, whether at the molecular, cellular, or whole organism level. Topics of interest encompass a wide range, such as cancer, infectious diseases, neuroimmunology, autoimmune diseases, allergies, mucosal immunity, metabolic diseases, and homeostasis.