{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T17:14:12Z","timestamp":1792516452473,"version":"4.5.0"},"reference-count":46,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2022,4,13]],"date-time":"2022-04-13T00:00:00Z","timestamp":1649808000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81671005"],"award-info":[{"award-number":["81671005"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81974151"],"award-info":[{"award-number":["81974151"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81771093"],"award-info":[{"award-number":["81771093"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81991500"],"award-info":[{"award-number":["81991500"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81991502"],"award-info":[{"award-number":["81991502"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82101037"],"award-info":[{"award-number":["82101037"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>IgG4\u2010related sialadenitis (IgG4\u2010RS) 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\u2010RS\u2013related fibrosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The expression of senescence markers and proinflammatory cytokines in the submandibular glands (SMGs) of IgG4\u2010RS patients (n\u2009=\u200918) and controls (n\u2009=\u200914) was determined by proteomics, real\u2010time polymerase chain reaction, Western blotting, and immunohistochemistry. After interleukin\u20104 (IL\u20104) treatment, high\u2010throughput RNA sequencing was performed to identify the differentially expressed genes in SMG\u2010C6 cells. A glandular fibrosis model was established by the intraglandular injection of IL\u20104 into mouse SMGs (n\u2009=\u20098 per group).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Salivary acinar and ductal epithelial cells underwent senescence in IgG4\u2010RS patients, as indicated by the elevated activity of senescence\u2010associated \u03b2\u2010galactosidase, lipofuscin accumulation, enhanced expression of senescence markers (p53 and p16<jats:sup>INK4A<\/jats:sup>), and up\u2010regulation of senescence\u2010associated secretory phenotype factors. Moreover, there was a significant increase in IL\u20104 levels in SMGs from IgG4\u2010RS patients (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.01), which positively correlated with p16<jats:sup>INK4A<\/jats:sup> expression and the fibrosis score. Incubation with IL\u20104 exacerbated salivary epithelial cell senescence by increasing the expression of p16<jats:sup>INK4A<\/jats:sup> through the reactive oxygen species (ROS)\/p38 MAPK pathway. Supernatant collected from IL\u20104\u2013induced senescent SMG\u2010C6 cells enhanced fibroblast activation and matrix protein production (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05). Furthermore, injecting mice with IL\u20104 promoted fibrosis and senescence phenotypes in SMGs in vivo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The cellular senescence induced by IL\u20104 through the ROS\/p38 MAPK\u2010p16<jats:sup>INK4A<\/jats:sup> pathway promotes fibrogenesis in IgG4\u2010RS. Our data suggest that cellular senescence could serve as a novel therapeutic target for treating IgG4\u2010RS.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42052","type":"journal-article","created":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T04:11:42Z","timestamp":1639973502000},"page":"1070-1082","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Contribution of Interleukin\u20104\u2013Induced Epithelial Cell Senescence to Glandular Fibrosis in <scp>IgG4\u2010Related<\/scp> Sialadenitis"],"prefix":"10.1002","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7016-0016","authenticated-orcid":false,"given":"Sai\u2010Nan","family":"Min","sequence":"first","affiliation":[{"name":"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 Key Laboratory of Digital Stomatology, Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health, and NMPA Key Laboratory for Dental Materials  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng\u2010Qi","family":"Zhu","sequence":"additional","affiliation":[{"name":"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 Key Laboratory of Digital Stomatology, Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health, and NMPA Key Laboratory for Dental Materials  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang\u2010Di","family":"Mao","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Li","sequence":"additional","affiliation":[{"name":"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 Key Laboratory of Digital Stomatology, Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health, and NMPA Key Laboratory for Dental Materials  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tai","family":"Wei","sequence":"additional","affiliation":[{"name":"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 Key Laboratory of Digital Stomatology, Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health, and NMPA Key Laboratory for Dental Materials  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Mei","sequence":"additional","affiliation":[{"name":"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 Key Laboratory of Digital Stomatology, Research Center of Engineering and Technology for Computerized Dentistry Ministry of Health, and NMPA Key Laboratory for Dental Materials  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Peking University School of Basic Medical Sciences Key Laboratory 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