SIRT1下调CCL20抑制Th17细胞中枢神经浸润在多发性硬化中的保护作用

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that mainly affecting young adults. It has a high disability rate and no cure. It is urgent to study the pathogenesis of MS. CNS infiltration of Th17 cells is an important step in the pathogenesis of MS. Animal models showed that overexpression of SIRT1 inhibited Th17 cell infiltration, but its molecular mechanism is unknown. We have found that expression of CCL20 by astrocyte play an important role in CNS infiltration of Th17 cells. The activity of SIRT1 is negatively correlated with the level of CCL20 in peripheral blood of MS patients，and the expression of SIRT1 decreased, while CCL20 increased in brain tissue of animal models and inflammatory factor-activated astrocytes, suggesting that SIRT1 is a potential negative regulator of CCL20. Therefore, we hypothesize that SIRT1 can reduce CNS infiltration of Th17 cells and MS inflammation by down-regulating CCL20 expressed by astrocyte. In this study, we aim to study the protective effect and molecular mechanism of SIRT1 in inhibiting CNS infiltration of Th17 cells via CCL20 in MS pathogenesis through animal and cell models, and finally provide ideas for exploring the pathogenesis of MS and finding new drug targets.

多发性硬化（MS）是好发于青壮年的中枢神经系统(CNS)炎性脱髓鞘疾病，致残率高，目前仍无法治愈，深入研究MS发病机制迫在眉睫。Th17细胞CNS浸润是MS发病的重要环节。动物模型发现，过表达沉默调节蛋白1（SIRT1）可抑制Th17细胞浸润，但分子机制不详。我们已经发现，星形胶质细胞表达趋化因子CCL20在趋化Th17细胞CNS浸润中发挥重要作用，MS患者外周血SIRT1活性与CCL20水平呈负相关，动物模型脑组织及炎性因子活化的星形胶质细胞表达SIRT1降低，而CCL20升高，提示SIRT1是CCL20潜在的负调节因子。由此我们提出假设：SIRT1通过下调星形胶质细胞CCL20，减少Th17细胞CNS浸润及MS炎症反应。本课题拟通过动物模型及细胞模型，深入研究SIRT1通过CCL20抑制Th17细胞CNS浸润在MS发病中的保护作用及分子机制，最终为探寻MS发病机制及寻找新的药物靶点提供依据。

多发性硬化（multiple sclerosis，MS）和视神经脊髓炎谱系疾病（neuromyelitis optica disorder spectrum, NMOSD）是常见的中枢神经系统炎性脱髓鞘性自身免疫疾病（autoimmune disease,AID）。虽然此类疾病的治疗已经有了长足的进展，但接受治疗的患者仍可能出现复发和病情恶化，因此阐明此类CNS脱髓鞘疾病的致病机理对疾病的精准治疗具有重要意义。Th17细胞在此类疾病发病机制中发挥重要作用。.本研究进一步证实Th17细胞在中枢神经系统AID中的作用。临床研究部分我们探索了免疫吸附作为新技术治疗国人NMOSD的临床疗效，结果显示难治性NMOSD急性期激素冲击治疗无效后补救性使用免疫吸附治疗仍然能够临床获益。我们分析免疫吸附可能的作用机制是通过清除循环中的IgG和免疫复合物，抑制Th17细胞激活，发挥免疫调节作用。实验部分我们发现SIRT1可能部分通过抑制NF-κB转录活性下调星形胶质细胞趋化因子CCL20的表达，从而抑制外周Th17细胞CNS浸润，在神经系统脱髓鞘疾病如MS中发挥保护作用，为探索此类神经系统脱髓鞘疾病药物治疗新靶点提供理论依据。