Immunoglobulin G4-related sialadenitis (IgG4-RS) is an immune-mediated fibro-inflammatory disease and the pathogenesis is still not fully understood. The aim of this study was to explore the role and mechanism of interleukin-13 (IL-13) in the cellular senescence during the progress of IgG4-RS. We found that the expression of IL-13 and IL-13 receptor α1 (IL-13Rα1) as well as the number of senescent cells were significantly higher in the submandibular glands (SMGs) of IgG4-RS patients. IL-13 directly induced senescence as shown by the elevated activity of senescence-associated β-galactosidase (SA-β-gal), the decreased cell proliferation, and the upregulation of senescence markers (p53 and p16) and senescence-associated secretory phenotype (SASP) factors (IL-1β and IL-6) in SMG-C6 cells. Mechanistically, IL-13 increased the level of phosphorylated signal transducer and activator of transcription 6 (p-STAT6) and mitochondrial-reactive oxygen species (mtROS), while decreased the mitochondrial membrane potential, ATP level, and the expression and activity of superoxide dismutase 2 (SOD2). Notably, the IL-13-induced cellular senescence and mitochondrial dysfunction could be inhibited by pretreatment with either STAT6 inhibitor AS1517499 or mitochondria-targeted ROS scavenger MitoTEMPO. Moreover, IL-13 increased the interaction between p-STAT6 and cAMP-response element binding protein (CREB)-binding protein (CBP) and decreased the transcriptional activity of CREB on SOD2. Taken together, our findings revealed a critical role of IL-13 in the induction of salivary gland epithelial cell senescence through the elevated mitochondrial oxidative stress in a STAT6–CREB–SOD2-dependent pathway in IgG4-RS.

免疫球蛋白 G4 相关唾液腺炎 (IgG4-RS) 是一种免疫介导的纤维炎症性疾病，其发病机制仍不完全清楚。本研究旨在探讨白细胞介素13（IL-13）在IgG4-RS进展过程中细胞衰老中的作用和机制。我们发现 IgG4-RS 患者的下颌下腺 (SMGs) 中 IL-13 和 IL-13 受体α1 (IL-13Rα1) 的表达以及衰老细胞的数量显着升高。IL-13 直接诱导衰老，表现为衰老相关 β-半乳糖苷酶 (SA-β-gal) 活性升高、细胞增殖减少、衰老标志物（p53 和 p16）和衰老相关分泌表型上调。 SMG-C6 细胞中的 SASP) 因子（IL-1β 和 IL-6）。机械地，IL-13 增加磷酸化信号转导和转录激活因子 6 (p-STAT6) 和线粒体活性氧 (mtROS) 的水平，同时降低线粒体膜电位、ATP 水平以及超氧化物歧化酶 2 的表达和活性。 SOD2)。值得注意的是，用 STAT6 抑制剂 AS1517499 或线粒体靶向 ROS 清除剂 MitoTEMPO 预处理可以抑制 IL-13 诱导的细胞衰老和线粒体功能障碍。此外，IL-13 增加了 p-STAT6 和 cAMP 反应元件结合蛋白 (CREB) 结合蛋白 (CBP) 之间的相互作用，并降低了 CREB ​​对 SOD2 的转录活性。综合起来，