Hypothalamic CRH Neuronal Activation Triggers Splenic Cell Proliferation and Promotes Atherosclerosis

The development of atherosclerotic plaque in the arterial intima can cause cardiovascular and cerebrovascular diseases worldwide. Our previous study reported that widespread neuroimmune cardiovascular interfaces appeared in the adventitia of atherosclerotic plaque, establishing a structural artery-brain circuit. Hypothalamic corticotropin-releasing hormone (CRH) neurons play a pivotal role in regulating the stress response and peripheral neuro-immune response. However, it remains unclear whether hypothalamic CRH neurons can regulate atherosclerosis. Elevated levels of sympathetic neurotransmitters and immune cells in the blood of patients with myocardial infarction suggested a role for sympathetic nervous activation in validating and promoting immune cell proliferation. Activation of hypothalamic CRH neurons in ApoE knockout mice promoted atherosclerosis and adventitial inflammation. Single-cell immune repertoire sequencing analysis demonstrated that hypothalamic CRH neurons drove splenic Treg/Teff imbalance via the ADRß2-MAPK axis and reshaped immune interaction networks to promote early atherosclerotic inflammation. Cell proliferation labeling experiments proved that hypothalamic CRH neurons promoted splenic immune cell proliferation in the early stage of atherosclerosis. Stereotaxic injection of apoptotic viruses to eliminate hypothalamic CRH neurons and surgical ablation of splenic sympathetic signals reduced splenic immune cell proliferation and inflammatory responses, which contributing to the alleviation of atherosclerosis. In summary, our study demonstrates that hypothalamic CRH neurons triggered splenic cell proliferation and promoted atherosclerosis. Overall design: ApoE knockout mice subjected to either high-fat diet alone or high-fat diet combined with chronic restraint stress for 6 weeks. Single-cell suspension of spleen was obtained and analyzed using scRNA-seq.