Vagal neuroimmune axis modulates heart failure by limiting monocyte-derived inflammatory CCRL2 macrophage II

Autonomic neuronal dysfunction is associated with heart failure (HF). Here, we report that targeted vagal nerve stimulation (VNS) using optogenetics attenuates cardiac remodelling and HF induced by pressure overload. Unbiased approaches revealed that VNS decreased the proportion of the Ccrl2+ macrophage subset, which derived from myeloid monocytes and exhibited a distinct tumour necrosis factor-alpha (TNFa)-responsive, pro-hypertrophic, and profibrotic signature. Elimination of Ccrl2+ macrophages prevented cardiac remodelling and HF. Functional characterisation by Ccrl2+ macrophage-specific overexpression or global genetic loss of a7 nicotinic acetylcholine receptor (a7nAChR) highlighted its crucial contribution to VNS-mediated cardioprotection. Mechanistically, activation of a7nAChR inhibited the TNFa responsiveness through upregulated expression of the transcription factor NRF2. Cardiac Ccrl2+ macrophages and TNFa-responsive proteins were positively correlated with cardiac remodelling and dysfunction in humans. Finally, an a7nAChR agonist effectively blocked the development of HF. These results suggest that the vagal neuroimmune axis modulates heart failure and is a promising target for treatment. Overall design: We performed bulk RNA-sequencing (RNA-seq) and single-cell RNA-sequencing (scRNA-seq) 8 weeks after TAC. Bulk RNA-seq analysis of heart tissues identified 873 differentially expressed genes (DEGs) between Ctrl-TAC and VNS-TAC mice, and the significant pathways in the VNS-TAC group were mapped to 16 categories, most of which were involved in the immune response