Contribution of Interleukin‐4–Induced Epithelial Cell Senescence to Glandular Fibrosis in IgG4‐Related Sialadenitis. Issue 6 (13th April 2022)

• Record Type: Journal Article
• Authors: Min, Sai‐Nan; Zhu, Meng‐Qi; Mao, Xiang‐Di; Li, Wei; Wei, Tai; Mei, Mei; Zhang, Yan; Wu, Li‐Ling; Yu, Guang‐Yan; Cong, Xin
• Is Part Of: Arthritis & rheumatology. Volume 74:Issue 6(2022)
• Page Start: 1070
• Page End: 1082
• Publication Date: 2022-04-13
• Subjects: Arthritis -- Periodicals; Rheumatism -- Periodicals; 616.72
• DOI: 10.1002/art.42052
• Languages: English
• ISSNs: 2326-5191

Abstract

Abstract : Objective: IgG4‐related sialadenitis (IgG4‐RS) is a chronic fibroinflammatory disease characterized by glandular fibrosis and hyposalivation. This study was undertaken to explore the role of cellular senescence in the pathogenesis of IgG4‐RS–related fibrosis. Methods: The expression of senescence markers and proinflammatory cytokines in the submandibular glands (SMGs) of IgG4‐RS patients (n = 18) and controls (n = 14) was determined by proteomics, real‐time polymerase chain reaction, Western blotting, and immunohistochemistry. After interleukin‐4 (IL‐4) treatment, high‐throughput RNA sequencing was performed to identify the differentially expressed genes in SMG‐C6 cells. A glandular fibrosis model was established by the intraglandular injection of IL‐4 into mouse SMGs (n = 8 per group). Results: Salivary acinar and ductal epithelial cells underwent senescence in IgG4‐RS patients, as indicated by the elevated activity of senescence‐associated β‐galactosidase, lipofuscin accumulation, enhanced expression of senescence markers (p53 and p16 INK4A ), and up‐regulation of senescence‐associated secretory phenotype factors. Moreover, there was a significant increase in IL‐4 levels in SMGs from IgG4‐RS patients ( P < 0.01), which positively correlated with p16 INK4A expression and the fibrosis score. Incubation with IL‐4 exacerbated salivary epithelial cell senescence by increasing the expression of p16 INK4A through the reactive oxygen species (ROS)/p38 MAPK pathway. Supernatant collected from IL‐4–induced senescent SMG‐C6 cells enhanced fibroblast activation and matrix protein production ( P < 0.05). Furthermore, injecting mice with IL‐4 promoted fibrosis and senescence phenotypes in SMGs in vivo. Conclusion: The cellular senescence induced by IL‐4 through the ROS/p38 MAPK‐p16 INK4A pathway promotes fibrogenesis in IgG4‐RS. Our data suggest that cellular senescence could serve as a novel therapeutic target for treating IgG4‐RS.