HMGB1调控Th17极化在哮喘发病中的作用及机制

Asthma is an allergic airway inflammatory diseases, closely related with Th17 dysfunction. Non-eosinophilic asthma predominantly infiltrated by polymorphonuclear neutrophil (PMN) is the main types of asthma,and the abnormal Th17 polarization induce the occurrence of NEA. As the pathogenesis is unknown, its clinical efficacy is poor.Recent studies have shown that the high mobility protein 1 (HMGB1) expression is increased in asthmatic patients, and related with the abnormal Th17 polarization. Our previous study found that HMGB1 treated lung dendritic (DC) from mouse can induce Th0 to differentiate into Th17 in vitro. Therefore, we hypothesized that HMGB1 induced the abnormal Th17 polarization by acting on DC,involved in the occurrence of the NEA. To verify this hypothesis, we intend ①to identify the HMGB1 expression is clearly associated with the dendritic phenotype and Th17 polarization in mouse model of asthma; ②to confirm the roles and mechanisms of HMGB1 treated DC in the induction of Th17 polarization in vitro; ③ to interfere HMGB1 signal in vivo, and clarify the roles and mechanisms of HMGB1 in controling Th17 polarization via DC. Our study reveals the roles and mechanism of HMGB1 controling Th17 polarization in the pathogenesis of asthma, and provide the potential target for clinical treatment of NEA.

哮喘是气道变应性炎症疾病，与Th17功能异常密切相关。以中性粒细胞（PMN）浸润为主的非嗜酸性细胞性哮喘（NEA）是哮喘的主要类型，Th17异常极化是诱发NEA的关键。因其发病机制不明，临床疗效不佳。最新研究表明，哮喘患者高迁移率蛋白1（HMGB1）表达增加，并与Th17异常极化有关。我们前期研究发现：HMGB1作用的小鼠肺脏树突状细胞(DC)，体外可以诱导Th0分化为Th17。因此，我们推测：HMGB1通过作用于DC，诱导Th17的异常极化，参与了NEA的发生。为验证该假设，本项目拟①通过哮喘小鼠模型，明确HMGB1表达与DC表型、Th17极化的关联；②体外实验证实HMGB1作用的小鼠DC在诱导Th17极化中的作用；③体内实验干预HMGB1信号，阐明HMGB1通过DC调控Th17极化的机制。本课题首次揭示HMGB1调控Th17极化在哮喘发病中的作用和机制，为临床治疗NEA提供潜在的靶点。

背景：以中性粒细胞浸润为主的非嗜酸性细胞性哮喘是哮喘（NEA）的主要类型，临床治疗效果不佳。已知Th17极化是诱发NEA的关键，但其发病机制不明。.主要研究内容：本研究着重探讨HMGB1通过树突状细胞(DC)调控Th17极化在哮喘发病中的作用和机制。.重要结果：本研究通过哮喘小鼠模型实验，明确HMGB1表达与DC表型、Th17极化的关联；②体内外实验证实HMGB1作用的DC在诱导Th17极化中的作用，阐明HMGB1通过DC调控Th17极化的机制。.关键数据：HMGB1抗体、HMGB1-A box以及sRAGE通过抑制HMGB1信号通路，有效下调非嗜酸性细胞性哮喘小鼠Th17极化，减轻非嗜酸性细胞性哮喘小鼠气道炎症。.科学意义：本课题首次揭示HMGB1调控Th17极化在哮喘发病中的作用和机制，为临床治疗NEA提供潜在的靶点。