cGAS-STING信号通路调节NLRP3炎症小体参与自身免疫甲状腺炎发病的机制研究

Autoimmune thyroiditis (AIT) is a common disorder of the endocrine system with a high prevalence and extensive effects on health. But the specific molecular events are not clear yet. Our previous research has found that, the AIT thyroid-sourced dsDNA could induce pyroptosis and inflammation, with AIM2 inflammasome activation as an important approach but not the whole. Recent studies have shown that the cGAS-STING pathway could be activated by dsDNA and participate in regulating the NLRP3 inflammasome, which plays important roles in immune defense and inflammatory regulation. Our preliminary experiment indicates that the cGAS-STING pathway is a new target for AIT pathogenesis. This study will start from AIT clinical cases to figure out the expression changes of cGAS-STING and its association with disease index. Subsequent using of cell and animal model to explore the molecular mechanism of cGAS-STING regulating NLRP3 and the influence on AIT progression by gene knock-out and exogenous activation, respectively. The conclusion of this study will further improve the theoretical structure of AIT etiology, and provide insights for new therapeutic targets and strategies.

自身免疫甲状腺炎(AIT)是内分泌系统常见疾病，其患病率高、危害广泛，但发病机制仍不明晰。课题组前期发现，AIT甲状腺来源的dsDNA可通过活化AIM2炎症小体诱导细胞损伤和炎症发生，但仍存在其他激活途径。cGAS是新近发现的dsDNA专职识别受体，可通过STING调节NLRP3炎症小体活化，在免疫调控中发挥关键作用。我们前期实验发现cGAS-STING在AIT甲状腺表达增加，但其在AIT发病中的作用及机制尚不明确，国内外未见相关报道。本项目拟从临床病例分析cGAS-STING通路在AIT中的表达特点及其与临床指标的相关性，继以细胞实验探索cGAS-STING调节NLRP3炎症小体的分子机制，动物模型在体实验评估cGAS-STING基因敲除、外源性激活对甲状腺细胞损伤、淋巴细胞失衡及AIT进展的影响。此研究结论将进一步丰富AIT免疫病因学理论架构，为寻找新的治疗靶点和防治策略提供科学依据。

自身免疫甲状腺炎（AIT）在中国成年人群的患病率超过10%，是临床甲减和亚临床甲减的主要病因，但发病机制仍不明晰，目前尚无针对病因的治疗措施。本项目主要论证cGAS-STING信号通路在AIT发生发展过程中的作用，识别其主要调控途径和关键分子。.研究发现：（1）cGAS-cGAMP-STING信号通路在AIT患者甲状腺组织中呈高表达、高激活状态，cGAS表达水平与多种炎性细胞因子及趋化因子呈正相关，初步明确其在AIT中发挥促炎症作用。（2）体外细胞实验证实，TNF-α、IFN-γ促进甲状腺细胞表达cGAS、STING，TBK-1、NF-κB可能是其调控NLRP3炎症小体及下游细胞因子的关键分子，参与AIT中炎症反应级联的反馈环路形成。（3）沉默cGAS表达可降低NLRP3炎症小体表达及活性，在体实验证实，抑制cGAS表达可缓解AIT动物模型甲状腺组织炎症浸润。.本研究结论合理解释了AIT的器官特异性，将进一步完善AIT病因学理论体系，为其他器官特异性自身免疫病发病机制研究提供借鉴。cGAS可能成为AIT病因学治疗的潜在靶点，为科学防治提供理论基础。