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

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

doi:10.1016/j.immuni.2025.06.003

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

Immunity. 2025 Jun 20:S1074-7613(25)00272-9. doi: 10.1016/j.immuni.2025.06.003. Online ahead of print.

Authors

Guoqi Li¹, Congcong Zhang¹, Yang Li¹, Jie Yang¹, Jianing Wu¹, Yihui Shao¹, Ke Ma¹, Xinyu Zhang¹, Shuolin Zhu¹, Jie Du¹, Xin-Liang Ma², Liping Wang³, Zhuofeng Lin⁴, Ping Li⁵, Yulin Li⁶

Affiliations

¹ Beijing Anzhen Hospital of Capital Medical University, Beijing, China; Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China.
² Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
³ Shenzhen Institute of Advanced Technology, Shenzhen, China.
⁴ Innovation Center of Cardiometabolic Diseases, Guangdong medical university, Dongguan, China; The Affiliated Dongguan Songshan Lake Central Hospital, Dongguan, China. Electronic address: zlin@gdmu.edu.cn.
⁵ Beijing Anzhen Hospital of Capital Medical University, Beijing, China. Electronic address: doctorliping7511@sohu.com.
⁶ Beijing Anzhen Hospital of Capital Medical University, Beijing, China; Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China. Electronic address: lyllyl_1111@163.com.

PMID: 40580954
DOI: 10.1016/j.immuni.2025.06.003

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.

Keywords: brain-heart axis; heart failure; macrophages; neuroimmune.