Interleukin-13 Promotes Cellular Senescence Through Inducing Mitochondrial Dysfunction in IgG4-related Sialadenitis

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（mt ROS）, 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 Mito TEMPO. Moreover, IL-13 increased the interaction between p-STAT6 and c AMP-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.