{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T01:12:19Z","timestamp":1766970739874,"version":"3.48.0"},"reference-count":38,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T00:00:00Z","timestamp":1766707200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background\/Objectives: The Notch\u2013ADAM17 pathway is a fundamental signaling mechanism where ADAM17, a disintegrin and metalloprotease, cleaves the Notch receptor after the Notch receptor binds to a ligand. Crosstalk between Notch and ADAM17 is often altered in pathological situations. Alterations in Notch2 expression, in particular, appears to be correlated with the onset of various autoimmune diseases. In primary Sj\u00f6gren\u2019s disease (pSjD), an autoimmune disorder characterized by chronic inflammation, the role of ADAM17 has been extensively explored, but a correlation with Notch2 has not yet been evaluated. Methods: To analyze the gene and protein expression of Notch2 in pSjD and a possible correlation with ADAM17 expression and with the patient\u2019s inflammatory grade, we employed an integrated co-detection protocol to analyze salivary gland tissue sections by combining in situ hybridization (ISH) with immunohistochemistry (IHC). Results: combined ISH\/IHC allows us to demonstrate an increased expression of Notch2 mRNA and protein in pSjD salivary glands (SGs) biopsies, which appears correlated with an increased expression of ADAM17, both in acinar and duct cells and in infiltrating lymphocytes. Notch2\/ADAM17 expression is higher in biopsies of pSjD SGs characterized by a high degree of inflammation. Conclusions: this work demonstrates the correlated expression in pSjD SGs of ADAM17, which plays multiple roles in the pathogenesis of SjD, and Notch2, widely considered a key player in various inflammatory mechanisms, offering a starting point for future therapeutic interventions to investigate.<\/jats:p>","DOI":"10.3390\/jcm15010182","type":"journal-article","created":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T00:50:42Z","timestamp":1766969442000},"page":"182","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Correlated Expression of Notch2 and ADAM17 in Primary Sj\u00f6gren\u2019s Syndrome Salivary Glands"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8349-1121","authenticated-orcid":false,"given":"Margherita","family":"Sisto","sequence":"first","affiliation":[{"name":"Department of Translational Biomedicine and Neuroscience (DiBraiN), Section of Human Anatomy and Histology, University of Bari \u201cAldo Moro\u201d, Piazza Giulio Cesare 1, 70124 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1294-2391","authenticated-orcid":false,"given":"Sabrina","family":"Lisi","sequence":"additional","affiliation":[{"name":"Department of Translational Biomedicine and Neuroscience (DiBraiN), Section of Human Anatomy and Histology, University of Bari \u201cAldo Moro\u201d, Piazza Giulio Cesare 1, 70124 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4623-5406","authenticated-orcid":false,"given":"Roberto","family":"Tamma","sequence":"additional","affiliation":[{"name":"Department of Translational Biomedicine and Neuroscience (DiBraiN), Section of Human Anatomy and Histology, University of Bari \u201cAldo Moro\u201d, Piazza Giulio Cesare 1, 70124 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelina","family":"De Giorgis","sequence":"additional","affiliation":[{"name":"Department of Translational Biomedicine and Neuroscience (DiBraiN), Section of Human Anatomy and Histology, University of Bari \u201cAldo Moro\u201d, Piazza Giulio Cesare 1, 70124 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4792-3545","authenticated-orcid":false,"given":"Giuseppe","family":"Ingravallo","sequence":"additional","affiliation":[{"name":"Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), Section of Molecular Pathology, University of Bari \u201cAldo Moro\u201d, 70124 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5116-2484","authenticated-orcid":false,"given":"Mario","family":"Della Mura","sequence":"additional","affiliation":[{"name":"Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), Section of Molecular Pathology, University of Bari \u201cAldo Moro\u201d, 70124 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8458-8648","authenticated-orcid":false,"given":"Joana","family":"Sorino","sequence":"additional","affiliation":[{"name":"Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), Section of Molecular Pathology, University of Bari \u201cAldo Moro\u201d, 70124 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1287-4285","authenticated-orcid":false,"given":"Eliano","family":"Cascardi","sequence":"additional","affiliation":[{"name":"Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), Section of Molecular Pathology, University of Bari \u201cAldo Moro\u201d, 70124 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4768-8431","authenticated-orcid":false,"given":"Domenico","family":"Ribatti","sequence":"additional","affiliation":[{"name":"Department of Translational Biomedicine and Neuroscience (DiBraiN), Section of Human Anatomy and Histology, University of Bari \u201cAldo Moro\u201d, Piazza Giulio Cesare 1, 70124 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Parambath, S., Selvraj, N.R., Venugopal, P., and Aradhya, R. (2024). Notch Signaling: An Emerging Paradigm in the Pathogenesis of Reproductive Disorders and Diverse Pathological Conditions. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25105423"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3030","DOI":"10.1111\/febs.16815","article-title":"Notch signalling: Multifaceted role in development and disease","volume":"291","author":"Sachan","year":"2024","journal-title":"FEBS J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1038\/nrm2009","article-title":"Notch signalling: A simple pathway becomes complex","volume":"7","author":"Bray","year":"2006","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s12929-021-00732-8","article-title":"Notching up knowledge on molecular mechanisms of skin fibrosis: Focus on the multifaceted Notch signalling pathway","volume":"28","author":"Condorelli","year":"2021","journal-title":"J. Biomed. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"8242","DOI":"10.1073\/pnas.1511236113","article-title":"Epithelial Notch signaling regulates lung alveolar morphogenesis and airway epithelial integrity","volume":"113","author":"Tsao","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1038\/s41423-025-01318-2","article-title":"Notch2-expressing CD4+ T cells attain immunoregulatory functions during autoimmune inflammation","volume":"22","author":"Bae","year":"2025","journal-title":"Cell Mol. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"111069","DOI":"10.1016\/j.intimp.2023.111069","article-title":"Long-term consequences of regulatory T-cell-specific knockout of Notch2 in immune homeostasis","volume":"124","author":"Fan","year":"2023","journal-title":"Int. Immunopharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2032","DOI":"10.1016\/j.bcp.2010.07.010","article-title":"Interestingly, Inflammation dysregulates Notch signaling in endothelial cells (implication of Notch2 and Notch4 to endothelial dysfunction","volume":"80","author":"Quillard","year":"2010","journal-title":"Biochem. Pharmacol."},{"key":"ref_9","first-page":"305","article-title":"Molecular cues for development and regeneration of salivary glands","volume":"29","author":"Liu","year":"2014","journal-title":"Histol. Histopathol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1152\/physrev.00005.2017","article-title":"Notch Signaling in Development, Tissue Homeostasis, and Disease","volume":"97","author":"Siebel","year":"2017","journal-title":"Physiol Rev."},{"key":"ref_11","first-page":"31","article-title":"NFkappaB2 (p52) promoter activation via Notch signaling pathway in rheumatoid synoviocytes","volume":"7","author":"Nakazawa","year":"2001","journal-title":"Int. J. Mol. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"7796","DOI":"10.1038\/sj.onc.1206965","article-title":"Induction of Notch signaling by tumor necrosis factor in rheumatoid synovial fibroblasts","volume":"22","author":"Ando","year":"2003","journal-title":"Oncogene"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"26","DOI":"10.3109\/03009740903124424","article-title":"Expression analysis of Notch-related molecules in peripheral blood T helper cells of patients with rheumatoid arthritis","volume":"39","author":"Jiao","year":"2010","journal-title":"Scand. J. Rheumatol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1007\/s00776-005-0943-3","article-title":"Immunohistological localization of Notch receptors and their ligands Delta and Jagged in synovial tissues of rheumatoid arthritis","volume":"10","author":"Yabe","year":"2005","journal-title":"J. Orthop. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1007\/s002960100119","article-title":"Expression of notch homologues in the synovium of rheumatoid arthritis and osteoarthritis patients","volume":"21","author":"Ishii","year":"2001","journal-title":"Rheumatol. Int."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1002\/1529-0131(200107)44:7<1545::AID-ART278>3.0.CO;2-Q","article-title":"Role of Notch-1 intracellular domain in activation of rheumatoid synoviocytes","volume":"44","author":"Nakazawa","year":"2001","journal-title":"Arthritis Rheum."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1136\/annrheumdis-2013-203467","article-title":"Inhibition of notch signalling ameliorates experimental inflammatory arthritis","volume":"74","author":"Park","year":"2015","journal-title":"Ann. Rheum. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1038\/ki.2010.172","article-title":"Expression of Notch pathway proteins correlates with albuminuria, glomerulosclerosis, and renal function","volume":"78","author":"Murea","year":"2010","journal-title":"Kidney Int."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"6465","DOI":"10.4049\/jimmunol.0904016","article-title":"Blockade of Notch1 signaling alleviates murine lupus via blunting macrophage activation and M2b polarization","volume":"184","author":"Zhang","year":"2010","journal-title":"J. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1136\/ard.2010.134742","article-title":"Notch signalling regulates fibroblast activation and collagen release in systemic sclerosis","volume":"70","author":"Dees","year":"2011","journal-title":"Ann. Rheum. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Horai, Y., Kurushima, S., Shimizu, T., Nakamura, H., and Kawakami, A. (2025). A Review of the Current Clinical Aspects of Sj\u00f6gren\u2019s Disease: Geographical Difference, Classification\/Diagnostic Criteria, Recent Advancements in Diagnostic Methods, and Molecular Targeted Therapy. J. Clin. Med., 14.","DOI":"10.3390\/jcm14155577"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.jmoldx.2011.08.002","article-title":"RNAscope: A novel in situ RNA analysis platform for formalin-fixed, paraffin-embedded tissues","volume":"14","author":"Wang","year":"2012","journal-title":"J. Mol. Diagn."},{"key":"ref_23","first-page":"559","article-title":"Explant culture of human submandibular gland epithelial cells: Evidence for ductal origin","volume":"2","author":"Sens","year":"1985","journal-title":"Lab. Investig."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1002\/art.39859","article-title":"2016 American College of Rheumatology\/European League Against Rheumatism classification criteria for primary Sj\u00f6gren\u2019s syndrome: A consensus and data-driven methodology involving three international patient cohorts","volume":"69","author":"Shiboski","year":"2017","journal-title":"Arthritis Rheumatol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/S0070-2153(10)92002-4","article-title":"Mechanistic insights into Notch receptor signaling from structural and biochemical studies","volume":"92","author":"Kovall","year":"2010","journal-title":"Curr. Top. Dev. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1038\/s41392-022-00934-y","article-title":"Notch signaling pathway: Architecture, disease, and therapeutics","volume":"7","author":"Zhou","year":"2022","journal-title":"Sig. Transduct. Target Ther."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Yakovleva, S., Knyazeva, A., Yunusova, A., Allayarova, E., Lanshakov, D., Malashicheva, A., and Shnaider, T. (2025). Functional Divergence of NOTCH1 and NOTCH2 in Human Cerebral Organoids Reveals Receptor-Specific Roles in Early Corticogenesis. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26157309"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.imlet.2014.08.008","article-title":"ADAM17 at the interface between inflammation and autoimmunity","volume":"162","author":"Lisi","year":"2014","journal-title":"Immunol. Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/gene.2012.9","article-title":"Sj\u00f6gren\u2019s syndrome pathological neovascularization is regulated by VEGF-A-stimulated TACE-dependent crosstalk between VEGFR2 and NF-\u03baB","volume":"13","author":"Sisto","year":"2012","journal-title":"Genes Immun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3540","DOI":"10.4049\/jimmunol.0803588","article-title":"Ectopic germinal centers are rare in Sjogren\u2019s syndrome salivary glands and do not exclude autoreactive B cells","volume":"182","author":"Devauchelle","year":"2009","journal-title":"J. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.jaut.2012.01.016","article-title":"Role of Toll-like receptors in primary Sj\u00f6gren\u2019s syndrome with a special emphasis on B-cell maturation within exocrine tissues","volume":"39","author":"Guerrier","year":"2012","journal-title":"J. Autoimmun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1084\/jem.20120904","article-title":"The coding genome of splenic marginal zone lymphoma: Activation of NOTCH2 and other pathways regulating marginal zone development","volume":"209","author":"Rossi","year":"2012","journal-title":"J. Exp. Med."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Kuksin, C.A., and Minter, L.M. (2015). The Link between Autoimmunity and Lymphoma: Does NOTCH Signaling Play a Contributing Role?. Front. Oncol., 5.","DOI":"10.3389\/fonc.2015.00051"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s13619-020-00072-2","article-title":"The interaction of Notch and Wnt signaling pathways in vertebrate regeneration","volume":"10","author":"Gao","year":"2021","journal-title":"Cell Regen."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.tcb.2011.10.002","article-title":"Coordinating developmental signaling: Novel roles for the Hippo pathway","volume":"22","author":"Varelas","year":"2012","journal-title":"Trends Cell Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"100248","DOI":"10.1016\/j.jtauto.2024.100248","article-title":"Single-cell transcriptomic analysis uncovers heterogeneity in the labial gland microenvironment of primary Sj\u00f6gren\u2019s syndrome","volume":"9","author":"Huang","year":"2024","journal-title":"J. Transl. Autoimmun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1002\/acr2.11082","article-title":"Gene expression profiles in primary Sj\u00f6gren\u2019s Syndrome with and without systemic manifestations","volume":"1","author":"Vitali","year":"2019","journal-title":"ACR Open Rheumatol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Peck, A.B., Nguyen, C.Q., and Ambrus, J.L. (2022). A MZB Cell Activation Profile Present in the Lacrimal Glands of Sj\u00f6gren\u2019s Syndrome-Susceptible C57BL\/6.NOD-Aec1Aec2 Mice Defined by Global RNA Transcriptomic Analyses. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23116106"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/1\/182\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T01:10:04Z","timestamp":1766970604000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/1\/182"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,26]]},"references-count":38,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["jcm15010182"],"URL":"https:\/\/doi.org\/10.3390\/jcm15010182","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,26]]}}}