循环外泌体miR-150负性调控Bregs在多发性硬化的作用及机制研究

Studies have shown that the percentage of Bregs in peripheral blood of patients with multiple sclerosis (MS) is down-regulated, but the mechanism is still unclear. Preliminary results showed that circulating exosomes in MS patients significantly inhibited the percentage of Bregs. Through miRNA microarray, increased expression of circulating exosomes miR-150 in MS patients was found to be negatively correlated with the percentage of Bregs, and our recent study showed that miR-150 knockdown can improve EAE symptoms and inhibit B cell down-regulation. Bioinformatics analysis and miRNA pull down experiment revealed that miR-150 targets both FOXP1 and FBXW 11, which have been shown to enhance β-catenin signaling and promote IL-10 expression. We propose hypothesis that circulating exosomes release miR-150 during MS disease process, targeting FOXP1/FBXW11-β-catenin signaling, and then negatively regulating the differentiation of Bregs and the secretion of IL-10, ultimately promoting the progression of MS. This study intends to explore the mechanism by which exosomes-derived miR-150 promotes MS disease at cellular level, animal level and clinical samples. The implementation of this program provides a potential strategy for drug development and treatment of MS with Bregs as a target.

促进调节性B细胞(Bregs)分泌IL-10、维持免疫稳态是治疗多发性硬化（MS）的研究热点。MS患者外周血Bregs比例下调，但机制尚不清楚。预实验显示MS患者循环外泌体miR-150表达增加且与Bregs百分比呈负相关，而申请者已证实敲除miR-150改善EAE症状并抑制B细胞下调。通过miRNA pull down实验发现miR-150靶向FOXP1和FBXW11，后者可增强β-catenin信号促进IL-10的表达。本课题遂提出假设: MS患者循环外泌体释放miR-150，靶向抑制FOXP1/FBXW11-β-catenin信号负性调控Bregs分化以及IL-10的分泌，促进MS病程进展。本课题拟从细胞水平、动物水平以及临床样本分析，展开循环外泌体来源miR-150在MS中的作用机制探讨。本项目的实施为靶向Bregs治疗MS提供潜在策略，具有重要的临床意义。

促进调节性B细胞(Bregs)分泌IL-10、维持免疫稳态是靶向B细胞亚群治疗多发性硬化（MS）的研究热点。研究表明MS患者外周血Bregs表达下调，但机制尚不清楚。实验显示MS患者循环外泌体显著抑制Bregs百分比。通过miRNA基因芯片，发现MS患者循环外泌体miR-150表达增加并与Bregs百分比呈负相关。申请者前期研究已表明miR-150-/- 可改善EAE症状、并抑制B细胞下调。通过生物信息分析和miRNA pull down实验发现miR-150同时靶向FOXP1和FBXW 11，后者已明确可增强β-catenin信号促进IL-10的表达。因此，本课题主要发现MS疾病进程中循环外泌体释放miR-150，靶向抑制FOXP1/FBXW11-β-catenin信号，进而负性调控Bregs的分化以及IL-10的分泌，最终促进MS病程进展。本课题从细胞水平、动物水平以及临床样本分析，系统地展开外泌体来源miR-150在MS疾病进程中的作用机制探讨。本课题的实施为以Bregs为靶点的药物开发和MS的治疗提供潜在策略, 具有重要的临床应用价值。

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