Interleukin-13 promotes cellular senescence through inducing mitochondrial dysfunction in IgG4-related sialadenitis.
10.1038/s41368-022-00180-6
- Author:
Mengqi ZHU
1
;
Sainan MIN
1
;
Xiangdi MAO
2
;
Yuan ZHOU
3
;
Yan ZHANG
2
;
Wei LI
1
;
Li LI
2
;
Liling WU
2
;
Xin CONG
4
;
Guangyan YU
5
Author Information
1. Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China.
2. Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China.
3. Department of Biomedical Informatics, Peking University School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China.
4. Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China. congxin@bjmu.edu.cn.
5. Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, China. gyyu@263.net.
- Publication Type:Research Support, Non-U.S. Gov't
- MeSH:
Cellular Senescence/genetics*;
Humans;
Immunoglobulin G/metabolism*;
Interleukin-13/pharmacology*;
Mitochondria/metabolism*;
Sialadenitis/metabolism*
- From:
International Journal of Oral Science
2022;14(1):29-29
- CountryChina
- Language:English
-
Abstract:
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.
