{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T16:31:16Z","timestamp":1783355476333,"version":"3.54.6"},"reference-count":59,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2023,4,3]],"date-time":"2023-04-03T00:00:00Z","timestamp":1680480000000},"content-version":"vor","delay-in-days":2,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["R01DE017102"],"award-info":[{"award-number":["R01DE017102"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["R01DE022765"],"award-info":[{"award-number":["R01DE022765"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["R01DE031716"],"award-info":[{"award-number":["R01DE031716"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp; Translational Med"],"published-print":{"date-parts":[[2023,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Primary Sjogren's syndrome (pSS) is a systemic autoimmune disease that is embodied by the loss of salivary gland function and immune cell infiltration, but the mechanism(s) are still unknown. The aim of this study was to understand the mechanisms and identify key factors that leads to the development and progression of pSS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Immunohistochemistry staining, FACS analysis and cytokine levels were used to detect immune cells infiltration and activation in salivary glands. RNA sequencing was performed to\u00a0identify the molecular mechanisms involved in the development of pSS. The function assays include in vivo saliva collection along with calcium imaging and electrophysiology on isolated salivary gland cells in mice models of pSS. Western blotting, real\u2010time PCR, alarmin release, and immunohistochemistry was performed to identify the channels involved in salivary function in pSS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We provide evidence that loss of Ca<jats:sup>2+<\/jats:sup> signaling precedes a decrease in saliva secretion and\/or immune cell infiltration in IL14\u03b1, a mouse model for pSS. We also showed that Ca<jats:sup>2+<\/jats:sup> homeostasis was mediated by transient receptor potential canonical\u20101 (TRPC1) channels and inhibition of TRPC1, resulting in the loss of salivary acinar cells, which promoted alarmin release essential for immune cell infiltration\/release of pro\u2010inflammatory cytokines. In addition, both IL14\u03b1 and samples from human pSS patients showed a decrease in TRPC1 expression and increased acinar cell death. Finally, paquinimod treatment in IL14\u03b1 restored Ca<jats:sup>2+<\/jats:sup> homeostasis that inhibited alarmin release thereby reverting the pSS phenotype.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These results indicate that loss of Ca<jats:sup>2+<\/jats:sup> signaling is one of the initial factors, which induces loss of salivary gland function along with immune infiltration that exaggerates pSS. Importantly, restoration of Ca<jats:sup>2+<\/jats:sup> signaling upon paquinimod treatment reversed the pSS phenotype thereby inhibiting the progressive development of pSS.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.1228","type":"journal-article","created":{"date-parts":[[2023,4,3]],"date-time":"2023-04-03T07:27:54Z","timestamp":1680506874000},"source":"Crossref","is-referenced-by-count":8,"title":["Targeting alarmin release reverses Sjogren's syndrome phenotype by revitalizing Ca<sup>2+<\/sup> signalling"],"prefix":"10.1002","volume":"13","author":[{"given":"Yuyang","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Periodontics School of Dentistry University of Texas Health Science Center San Antonio  San Antonio Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viviane","family":"Nascimento Da Conceicao","sequence":"additional","affiliation":[{"name":"Department of Periodontics School of Dentistry University of Texas Health Science Center San Antonio  San Antonio Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arun","family":"Chauhan","sequence":"additional","affiliation":[{"name":"Department of Developmental Dentistry School of Dentistry University of Texas Health Science Center San Antonio  San Antonio Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pramod","family":"Sukumaran","sequence":"additional","affiliation":[{"name":"Department of Periodontics School of Dentistry University of Texas Health Science Center San Antonio  San Antonio Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pooja","family":"Chauhan","sequence":"additional","affiliation":[{"name":"Department of Developmental Dentistry School of Dentistry University of Texas Health Science Center San Antonio  San Antonio Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian L.","family":"Ambrus","sequence":"additional","affiliation":[{"name":"Division of Allergy, Immunology, and Rheumatology Department of Medicine School of Medicine and Biomedical Sciences State University of New York  Buffalo New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arjan","family":"Vissink","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery University of Groningen and University Medical Center Groningen  Groningen The\u00a0Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frans G. 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