骶神经电刺激通过ACh诱生CD103+DC改善肠道炎症的机制研究

Inflammatory bowel disease is a chronic inflammatory disorder associated with immune dysfunction. Previous studies have shown that cholinergic nerve has anti-inflammatory effect, and stimulation of vagus nerve can relieve IBD disease activity. However, clinical application is limited due to its cardiovascular side effects. Sacral nerve stimulation due to its side effects are widely used in certain diseases of the intestinal tract, but the effectiveness of IBD remains unknown. Our previous study demonstrated that SNS significantly reduced the DAI of IBD. In addition, the inflammatory cytokines and histological changes were significantly improved. Further study showed that CD103+DC in mesenteric lymph nodes increased significantly after SNS treatment, and ACh expression was also significantly increased. Combined with DC expression of ACh receptor α7nAChR, and ACh promotes CD103+DC conversion in vitro experiment.we speculate that SNS might ameliorate the development of colitis by promoting the CD103+DC conversion. With the help of animal models,our project aims to clarify the mechanism by which SNS ameliorates the colitis through regulating the CD103+DC, and provide a reliable theoretical basis for the new strategies of IBD treatment.

炎症性肠病（IBD）是一种慢性肠道炎症疾病，与免疫紊乱密切相关，目前治疗困难。研究发现胆碱能神经具有抗炎效应，我们的工作证实迷走神经电刺激（VNS）可改善肠道炎症，但因其兴奋全身副交感的副作用，临床应用受限。骶神经电刺激（SNS）因主要是局部作用，副作用小，较VNS更适合临床应用。我们前期研究发现：肠炎模型小鼠在SNS治疗后，肠炎活动度和和肠道组织中的炎性因子表达明显下降；肠道组织ACh表达明显升高；同时在肠系膜淋巴结中，具有诱导Treg功能的耐受型CD103+DC明显增加。结合DC表达ACh受体α7nAChR，且ACh促进DC向CD103+DC分化的体外实验证据。申报者推测，SNS可能通过激活胆碱能神经通路增加肠道ACh促进耐受型CD103+DC分化，进而诱生Treg抑制肠道免疫炎症。为证实上述假设，本项目拟借助动物模型，从分子、细胞和整体水平探讨SNS缓解肠道炎症的作用及其机制。

炎症性肠病（IBD）是一种慢性肠道炎症疾病，认为免疫紊乱诱发的炎症是引起肠道损伤的关键因素治疗困难，探索安全的治疗措施是目前控制IBD免疫炎症的关键。肠炎模型小鼠骶神经电刺激（SNS）治疗后，肠炎活动度和和肠道组织中的炎性因子表达明显下降；肠道组织ACh表达明显升高；胆碱能神经具有抗炎效应，但迷走神经因其兴奋全身副交感的副作用，临床应用受限。SNS因体表操作方便副作用小，较VNS更适合临床应用。我们研究表明ENS与胃肠道肌层巨噬细胞活化状态密切相关，且去甲肾上腺素能神经信号和胆碱能神经信号均可以调节胃肠道肌层巨噬细胞的活化状态。本研究证实骶神经电刺激信号可通过脊神经传入-迷走神经传出途径改善肠道炎症，通过激活胆碱能通路，即骶神经信号上传-脊椎-大脑-下传至迷走传出通路，从而通过胆碱能通路间接促进肠道组织中ACh的释放增加。确认骶神经电刺激可以通过介导肠黏膜神经的活化、神经纤维密度及分化等可塑性改变来调控肠炎的发展，参与慢性DSS结肠炎肠神经免疫的作用机制。证实SNS对肠道炎症具有免疫调控作用，其机制是通过激活胆碱能通路→ACh↑神经信号→调整巨噬细胞活化ENS→促进Treg分化→抑制异常免疫应答产生的炎症”。本研究借助了动物模型，从分子、细胞和整体水平证实了SNS减轻肠道炎症的神经免疫作用机制。