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

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 attempted to activate the vagal-a7nAChR axis via pharmacological tools and investigated which type of therapy, enhancing ACh contents or activating a7nAChR, was more effective for treating HF. The selective a7nAChR agonist EVP-6124 was used, as it is well tolerated and has successfully progressed to phase III clinical trials. As well, the acetylcholinesterase inhibitor donepezil was used, as it improves heart dysfunction in rats with acute myocardial infarction. To determine whether drug treatment could mitigate the progression of HF after cardiac remodelling, WT mice that underwent TAC for 4 weeks were randomised into three treatment groups administered saline, donepezil (5 mg/kg/day), or EVP-6124 (2 mg/kg/day)