{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T15:19:56Z","timestamp":1787066396185,"version":"build-2736575974"},"reference-count":54,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2024,5,30]],"date-time":"2024-05-30T00:00:00Z","timestamp":1717027200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["DE032911"],"award-info":[{"award-number":["DE032911"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Oklahoma Medical Research Foundation","award":["DE032911"],"award-info":[{"award-number":["DE032911"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Elevated oxidative stress can play a pivotal role in autoimmune diseases by exacerbating inflammatory responses and tissue damage. In Sj\u00f6gren\u2019s disease (SjD), the contribution of oxidative stress in the disease pathogenesis remains unclear. To address this question, we created mice with a tamoxifen-inducible conditional knockout (KO) of a critical antioxidant enzyme, superoxide dismutase 2 (Sod2), in the salivary glands (i-sg-Sod2 KO mice). Following tamoxifen treatment, Sod2 deletion occurred primarily in the ductal epithelium, and the salivary glands showed a significant downregulation of Sod2 expression. At twelve weeks post-treatment, salivary glands from the i-sg-Sod2 KO mice exhibited increased 3-Nitrotyrosine staining. Bulk RNA-seq revealed alterations in gene expression pathways related to ribosome biogenesis, mitochondrial function, and oxidative phosphorylation. Significant changes were noted in genes characteristic of salivary gland ionocytes. The i-sg-Sod2 KO mice developed reversible glandular hypofunction. However, this functional loss was not accompanied by glandular lymphocytic foci or circulating anti-nuclear antibodies. These data demonstrate that although localized oxidative stress in salivary gland ductal cells was insufficient for SjD development, it induced glandular dysfunction. The i-sg-Sod2 KO mouse resembles patients classified as non-Sj\u00f6gren\u2019s sicca and will be a valuable model for deciphering oxidative-stress-mediated glandular dysfunction and recovery mechanisms.<\/jats:p>","DOI":"10.3390\/ijms25115983","type":"journal-article","created":{"date-parts":[[2024,5,30]],"date-time":"2024-05-30T10:42:34Z","timestamp":1717065754000},"page":"5983","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Deleting Mitochondrial Superoxide Dismutase 2 in Salivary Gland Ductal Epithelial Cells Recapitulates Non-Sj\u00f6gren\u2019s Sicca Syndrome"],"prefix":"10.3390","volume":"25","author":[{"given":"Joanna A.","family":"Papinska","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Oklahoma University Health Sciences Center, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7301-5324","authenticated-orcid":false,"given":"Justyna","family":"Dur\u015blewicz","sequence":"additional","affiliation":[{"name":"Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harini","family":"Bagavant","sequence":"additional","affiliation":[{"name":"Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Umesh S.","family":"Deshmukh","sequence":"additional","affiliation":[{"name":"Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1056\/NEJMcp1702514","article-title":"Primary Sj\u00f6gren\u2019s Syndrome","volume":"378","author":"Mariette","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/bs.ircmb.2018.05.006","article-title":"Mitochondria and Reactive Oxygen Species in Aging and Age-Related Diseases","volume":"340","author":"Giorgi","year":"2018","journal-title":"Int. Rev. Cell Mol. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1161\/CIRCRESAHA.117.311401","article-title":"Reactive Oxygen Species in Metabolic and Inflammatory Signaling","volume":"122","author":"Forrester","year":"2018","journal-title":"Circ. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2857","DOI":"10.4049\/jimmunol.1301539","article-title":"Processes of Sterile Inflammation","volume":"191","author":"Shen","year":"2013","journal-title":"J. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Porcheri, C., and Mitsiadis, T.A. (2019). Physiology, Pathology and Regeneration of Salivary Glands. Cells, 8.","DOI":"10.3390\/cells8090976"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"141","DOI":"10.3109\/10715762.2011.645206","article-title":"Oxidative Stress, as Measured by Protein Oxidation, Is Increased in Primary Sj\u00f8gren\u2019s Syndrome","volume":"46","author":"Norheim","year":"2012","journal-title":"Free Radic. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"270","DOI":"10.5937\/jomb0-27281","article-title":"Thiol\/Disulfide Homeostasis Impaired in Patients with Primary Sj\u00f6gren\u2019s Syndrome","volume":"40","author":"Yilmaz","year":"2021","journal-title":"J. Med. Biochem."},{"key":"ref_8","first-page":"2035","article-title":"Thioredoxin May Exert a Protective Effect against Tissue Damage Caused by Oxidative Stress in Salivary Glands of Patients with Sj\u00f6gren\u2019s Syndrome","volume":"34","author":"Kurimoto","year":"2007","journal-title":"J. Rheumatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1159\/000098211","article-title":"Possible Involvement of Oxidative Stress in Salivary Gland of Patients with Sjogren\u2019s Syndrome","volume":"73","author":"Ryo","year":"2006","journal-title":"Pathobiology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1167\/iovs.12-10325","article-title":"Evaluation of Lipid Oxidative Stress Status in Sj\u00f6gren Syndrome Patients","volume":"54","author":"Wakamatsu","year":"2013","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_11","first-page":"997","article-title":"The Role of Conjunctival Epithelial Cell Xanthine Oxidoreductase\/Xanthine Oxidase in Oxidative Reactions on the Ocular Surface of Dry Eye Patients with Sj\u00f6gren\u2019s Syndrome","volume":"22","author":"Ardan","year":"2007","journal-title":"Histol. Histopathol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.niox.2007.04.006","article-title":"Nitric Oxide Synthase Induction and Cytotoxic Nitrogen-Related Oxidant Formation in Conjunctival Epithelium of Dry Eye (Sj\u00f6gren\u2019s Syndrome)","volume":"17","author":"Ardan","year":"2007","journal-title":"Nitric Oxide"},{"key":"ref_13","first-page":"1477","article-title":"Decreased Expression of Antioxidant Enzymes in the Conjunctival Epithelium of Dry Eye (Sj\u00f6gren\u2019s Syndrome) and Its Possible Contribution to the Development of Ocular Surface Oxidative Injuries","volume":"23","author":"Ardan","year":"2008","journal-title":"Histol. Histopathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"16047","DOI":"10.1038\/nrdp.2016.47","article-title":"Sj\u00f6gren Syndrome","volume":"2","author":"Baldini","year":"2016","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2021","DOI":"10.1002\/art.30381","article-title":"Associations between Salivary Gland Histopathologic Diagnoses and Phenotypic Features of Sj\u00f6gren\u2019s Syndrome among 1,726 Registry Participants","volume":"63","author":"Daniels","year":"2011","journal-title":"Arthritis Rheum."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1093\/rheumatology\/41.4.416","article-title":"Dry Eyes and Mouth Syndrome\u2014A Subgroup of Patients Presenting with Sicca Symptoms","volume":"41","author":"Price","year":"2002","journal-title":"Rheumatology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e002119","DOI":"10.1136\/rmdopen-2021-002119","article-title":"Sj\u00f6gren\u2019s and Non-Sj\u00f6gren\u2019s Sicca Share a Similar Symptom Burden but with a Distinct Symptom-Associated Proteomic Signature","volume":"8","author":"Pucino","year":"2022","journal-title":"RMD Open"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1002\/ar.23569","article-title":"Overview of Human Salivary Glands: Highlights of Morphology and Developing Processes","volume":"300","author":"Teshima","year":"2017","journal-title":"Anat. Rec."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1177\/00220345870660020201","article-title":"The Proper Role of Nerves in Salivary Secretion: A Review","volume":"66","author":"Garrett","year":"1987","journal-title":"J. Dent. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1159\/000358781","article-title":"Salivary Secretion: Mechanism and Neural Regulation","volume":"24","author":"Proctor","year":"2014","journal-title":"Monogr. Oral. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Kim, Y.-J. (2023). Xerostomia and Its Cellular Targets. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24065358"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1047235","DOI":"10.3389\/fdmed.2023.1047235","article-title":"Xerogenic Medications May Contribute to Decreased Unstimulated Salivary Flow in Patients with Oral Burning and\/or Gastro-Esophageal Reflux Disease","volume":"4","author":"Sangalli","year":"2023","journal-title":"Front. Dent. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1016\/S0006-291X(02)00933-6","article-title":"Model Mice for Tissue-Specific Deletion of the Manganese Superoxide Dismutase (MnSOD) Gene","volume":"296","author":"Ikegami","year":"2002","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Maruyama, E.O., Aure, M.H., Xie, X., Myal, Y., Gan, L., and Ovitt, C.E. (2016). Cell-Specific Cre Strains For Genetic Manipulation in Salivary Glands. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0146711"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Nojima, K., Miyazaki, H., Hori, T., Vargova, L., and Oohashi, T. (2021). Assessment of Possible Contributions of Hyaluronan and Proteoglycan Binding Link Protein 4 to Differential Perineuronal Net Formation at the Calyx of Held. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.730550"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"137","DOI":"10.2147\/VHRM.S165173","article-title":"Paraoxonase (PON)-1: A Brief Overview on Genetics, Structure, Polymorphisms and Clinical Relevance","volume":"14","author":"Shunmoogam","year":"2018","journal-title":"Vasc. Health Risk Manag."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1152\/physiolgenomics.00161.2004","article-title":"The Gene Encoding Mouse Muc19: cDNA, Genomic Organization and Relationship to Smgc","volume":"19","author":"Culp","year":"2004","journal-title":"Physiol. Genom."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1369\/jhc.2008.952853","article-title":"Expression of Muc19\/Smgc Gene Products during Murine Sublingual Gland Development: Cytodifferentiation and Maturation of Salivary Mucous Cells","volume":"57","author":"Das","year":"2009","journal-title":"J. Histochem. Cytochem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1369\/jhc.2009.954891","article-title":"Tissue Distibution of Murine Muc19\/Smgc Gene Products","volume":"58","author":"Das","year":"2010","journal-title":"J. Histochem. Cytochem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/s00441-020-03205-w","article-title":"The Lack of Terminal Tubule Cells in the Submandibular Gland of Mice Deficient in Submandibular Gland Protein C","volume":"381","author":"Nakata","year":"2020","journal-title":"Cell Tissue Res."},{"key":"ref_31","unstructured":"(2024, April 05). NIDCR Salivary Gland Atlas, Available online: https:\/\/sgmap.nidcr.nih.gov\/sgmap\/sgexp.html."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.scr.2012.01.002","article-title":"Ascl3 Marks Adult Progenitor Cells of the Mouse Salivary Gland","volume":"8","author":"Elliott","year":"2012","journal-title":"Stem Cell Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"110663","DOI":"10.1016\/j.celrep.2022.110663","article-title":"A Mesenchymal to Epithelial Switch in Fgf10 Expression Specifies an Evolutionary-Conserved Population of Ionocytes in Salivary Glands","volume":"39","author":"Mauduit","year":"2022","journal-title":"Cell Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1915","DOI":"10.1083\/jcb.201708007","article-title":"Superoxide Dismutases: Dual Roles in Controlling ROS Damage and Regulating ROS Signaling","volume":"217","author":"Wang","year":"2018","journal-title":"J. Cell Biol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Laher, I. (2014). Systems Biology of Free Radicals and Antioxidants, Springer.","DOI":"10.1007\/978-3-642-30018-9"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1038\/ng1295-376","article-title":"Dilated Cardiomyopathy and Neonatal Lethality in Mutant Mice Lacking Manganese Superoxide-Dismutase","volume":"11","author":"Li","year":"1995","journal-title":"Nat. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1016\/j.freeradbiomed.2004.12.020","article-title":"Selective Neuronal Vulnerability and Inadequate Stress Response in Superoxide Dismutase Mutant Mice","volume":"38","author":"Lynn","year":"2005","journal-title":"Free Radic. Biol. Med."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Zhuang, A., Yang, C., Liu, Y., Tan, Y., Bond, S.T., Walker, S., Sikora, T., Laskowski, A., Sharma, A., and de Haan, J.B. (2021). SOD2 in Skeletal Muscle: New Insights from an Inducible Deletion Model. Redox Biol., 47.","DOI":"10.1016\/j.redox.2021.102135"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"103707","DOI":"10.1016\/j.isci.2021.103707","article-title":"Enterocyte Superoxide Dismutase 2 Deletion Drives Obesity","volume":"25","author":"Bovenga","year":"2022","journal-title":"iScience"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Bhaskaran, S., Kumar, G., Thadathil, N., Piekarz, K.M., Mohammed, S., Lopez, S.D., Qaisar, R., Walton, D., Brown, J.L., and Murphy, A. (2023). Neuronal Deletion of MnSOD in Mice Leads to Demyelination, Inflammation and Progressive Paralysis That Mimics Phenotypes Associated with Progressive Multiple Sclerosis. Redox Biol., 59.","DOI":"10.1016\/j.redox.2022.102550"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1177\/0022034518760855","article-title":"Activation of Stimulator of Interferon Genes (STING) and Sj\u00f6gren Syndrome","volume":"97","author":"Papinska","year":"2018","journal-title":"J. Dent. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4539","DOI":"10.1113\/JP285104","article-title":"Structural and Functional Analysis of Salivary Intercalated Duct Cells Reveals a Secretory Phenotype","volume":"601","author":"Wahl","year":"2023","journal-title":"J. Physiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.archoralbio.2018.11.001","article-title":"Hyperoxia Reduces Salivary Secretion by Inducing Oxidative Stress in Mice","volume":"98","author":"Tajiri","year":"2019","journal-title":"Arch. Oral. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Bagavant, H., Durslewicz, J., Pyclik, M., Makuch, M., Papinska, J.A., and Deshmukh, U.S. (2024). Age-Associated B Cell Infiltration in Salivary Glands Represents a Hallmark of Sj\u00f6gren\u2019s-like Disease in Aging Mice. GeroScience.","DOI":"10.1007\/s11357-024-01159-3"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1002\/art.39859","article-title":"2016 ACR-EULAR 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_46","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s42358-022-00255-2","article-title":"Clinical and Laboratory Evaluation of Sicca Complaints: Distinctive Aspects of Primary, Secondary and Non-Sjogren Syndrome","volume":"62","author":"Motta","year":"2022","journal-title":"Adv. Rheumatol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2063","DOI":"10.1038\/s41598-020-59078-0","article-title":"Patients with Non-Sj\u00f6gren\u2019s Sicca Report Poorer General and Oral Health-Related Quality of Life than Patients with Sj\u00f6gren\u2019s Syndrome: A Cross-Sectional Study","volume":"10","author":"Tashbayev","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2814","DOI":"10.3389\/fimmu.2019.02814","article-title":"JAK Inhibitors and Oxidative Stress Control","volume":"10","author":"Charras","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"543","DOI":"10.23736\/S0026-4725.18.04638-8","article-title":"Efficacy of Pycnogenol\u00ae Supplementation in Remission Phases of Sj\u00f6gren Syndrome","volume":"66","author":"Luzzi","year":"2018","journal-title":"Minerva Cardioangiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1002\/dvg.20335","article-title":"A Global Double-Fluorescent Cre Reporter Mouse","volume":"45","author":"Muzumdar","year":"2007","journal-title":"Genesis"},{"key":"ref_51","first-page":"57203","article-title":"A Method for the Measurement of Salivary Gland Function in Mice","volume":"131","author":"Bagavant","year":"2018","journal-title":"J. Vis. Exp."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Papinska, J., Bagavant, H., Gmyrek, G.B., and Deshmukh, U.S. (2020). Pulmonary Involvement in a Mouse Model of Sj\u00f6gren\u2019s Syndrome Induced by STING Activation. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21124512"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"16878","DOI":"10.1038\/s41598-017-17204-5","article-title":"QuPath: Open Source Software for Digital Pathology Image Analysis","volume":"7","author":"Bankhead","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1111\/j.1601-0825.2011.01839.x","article-title":"Activation of Innate Immunity Accelerates Sialoadenitis in a Mouse Model for Sj\u00f6gren\u2019s Syndrome-like Disease","volume":"17","author":"Nandula","year":"2011","journal-title":"Oral Dis."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/11\/5983\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:50:41Z","timestamp":1760107841000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/11\/5983"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,30]]},"references-count":54,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2024,6]]}},"alternative-id":["ijms25115983"],"URL":"https:\/\/doi.org\/10.3390\/ijms25115983","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,30]]}}}