白介素-13诱导的细胞衰老在IgG4相关性唾液腺炎中的作用及机制研究

IgG4相关性唾液腺炎（IgG4-RS）是近年来提出的自身免疫性疾病，发病机制不明。我们的预实验显示白介素-13（IL-13）在患者下颌下腺中显著升高，但其在细胞衰老及IgG4-RS中的作用不明。我们提出IL-13可能经下调线粒体调控因子PGC-1α引起线粒体功能异常，导致腺泡细胞衰老和IgG4-RS发生发展的科学假说。本项目拟在IgG4-RS患者的活检样本及培养的大鼠腺泡细胞上证实IL-13是致细胞衰老的重要因子；检测IL-13对培养细胞PGC-1α表达、线粒体结构、膜电位、活性氧及ATP生成的影响，明确线粒体损伤是介导IL-13诱导的细胞衰老的主要途径；通过工具药、敲低及过表达方法揭示PGC-1α是介导IL-13引起线粒体功能异常与细胞衰老的关键分子。该研究将揭示IL-13诱导的细胞衰老是IgG4-RS腺泡细胞损伤的新机制，并为探讨以清除衰老细胞为靶点治疗IgG4-RS提供新思路。

IgG4-related sialadenitis (IgG4-RS) is recently recognized as an autoimmune disease, however, its pathogenesis is unclear. Our preliminary experiments showed that interleukin-13 (IL-13) was obviously increased in the submandibular glands obtained from the patients with IgG4-RS, but its role in cellular senescence and IgG4-RS has not been elucidated. We hypothesized that the IL-13 might down-regulate peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a mitochondrial regulatory factor, to induce mitochondrial dysfunction, leading to cellular senescence and the development of IgG4-RS. In the samples from IgG4-RS patients and cultured rat acinar cells, we will investigate the effect of IL-13 on cellular senescence. Meanwhile, we will detect the effects of IL-13 on PGC-1α expression, mitochondrial structure, membrane potential, reactive oxygen species and ATP production to confirm that mitochondrial damage is an important pathway mediating IL-13-induced cellular senescence. Then, pharmacological activator, knockdown and overexpression of PGC-1α will be used to reveal that PGC-1α is a key molecule to mediate IL-13-induced mitochondrial dysfunction and cellular senescence. This study will clarify that IL-13-induced cellular senescence is a new pathogenic mechanism of IgG4-RS and provide new insight into the therapeutic strategy of IgG4-RS by targeting aging cells.