{"doi":"10.1016/j.omtn.2022.09.020","title":"Mitochondrial double-stranded RNAs as a pivotal mediator in the pathogenesis of Sjӧgren’s syndrome","abstract":"Sjӧgren’s syndrome (SS) is a systemic autoimmune disease that targets the exocrine glands, resulting in impaired saliva and tear secretion. To date, type I interferons (I-IFNs) are increasingly recognized as pivotal mediators in SS, but their endogenous drivers have not been elucidated. Here, we investigate the role of mitochondrial double-stranded RNAs (mt-dsRNAs) in regulating I-IFNs and other glandular phenotypes of SS. We find that mt-dsRNAs are elevated in the saliva and tears of SS patients (n = 73 for saliva and n = 16 for tears) and in salivary glands of non-obese diabetic mice with salivary dysfunction. Using the in-house-developed 3D culture of immortalized human salivary gland cells, we show that stimulation by exogenous dsRNAs increase mt-dsRNAs, activate the innate immune system, trigger I-IFNs, and promote glandular phenotypes. These responses are mediated via the Janus kinase 1 (JAK1)/signal transducer and activator of transcription (STAT) pathway. Indeed, a small chemical inhibitor of JAK1 attenuates mtRNA elevation and immune activation. We further show that muscarinic receptor ligand acetylcholine ameliorates autoimmune characteristics by preventing mt-dsRNA-mediated immune activation. Last, direct suppression of mt-dsRNAs reverses the glandular phenotypes of SS. Altogether, our study underscores the significance of mt-dsRNA upregulation in the pathogenesis of SS and suggests mt-dsRNAs as propagators of a pseudo-viral signal in the SS target tissue. Sjӧgren’s syndrome (SS) is a systemic autoimmune disease that targets the exocrine glands, resulting in impaired saliva and tear secretion. To date, type I interferons (I-IFNs) are increasingly recognized as pivotal mediators in SS, but their endogenous drivers have not been elucidated. Here, we investigate the role of mitochondrial double-stranded RNAs (mt-dsRNAs) in regulating I-IFNs and other glandular phenotypes of SS. We find that mt-dsRNAs are elevated in the saliva and tears of SS patients (n = 73 for saliva and n = 16 for tears) and in salivary glands of non-obese diabetic mice with salivary dysfunction. Using the in-house-developed 3D culture of immortalized human salivary gland cells, we show that stimulation by exogenous dsRNAs increase mt-dsRNAs, activate the innate immune system, trigger I-IFNs, and promote glandular phenotypes. These responses are mediated via the Janus kinase 1 (JAK1)/signal transducer and activator of transcription (STAT) pathway. Indeed, a small chemical inhibitor of JAK1 attenuates mtRNA elevation and immune activation. We further show that muscarinic receptor ligand acetylcholine ameliorates autoimmune characteristics by preventing mt-dsRNA-mediated immune activation. Last, direct suppression of mt-dsRNAs reverses the glandular phenotypes of SS. Altogether, our study underscores the significance of mt-dsRNA upregulation in the pathogenesis of SS and suggests mt-dsRNAs as propagators of a pseudo-viral signal in the SS target tissue.","journal":"Molecular Therapy — Nucleic Acids","year":2022,"id":240789,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":44,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9593,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":868907,"name":"Min-Seok Lee","orcid":"0000-0002-9180-7699","position":1,"is_corresponding":false},{"id":459906,"name":"Ahsan Ausaf Ali","orcid":"0000-0002-2040-8498","position":2,"is_corresponding":false},{"id":822143,"name":"Ye Rim Oh","orcid":null,"position":3,"is_corresponding":false},{"id":822144,"name":"Yong Seok Choi","orcid":null,"position":4,"is_corresponding":false},{"id":821758,"name":"Sujin Kim","orcid":"0000-0001-9088-3502","position":5,"is_corresponding":false},{"id":821759,"name":"Namseok Lee","orcid":"0000-0002-3291-6561","position":6,"is_corresponding":false},{"id":821760,"name":"Se Gwang Jang","orcid":"0000-0003-0518-5975","position":7,"is_corresponding":false},{"id":869411,"name":"Seonghyeon Park","orcid":null,"position":8,"is_corresponding":false},{"id":869412,"name":"Jin‐Haeng Chung","orcid":null,"position":9,"is_corresponding":false},{"id":821761,"name":"Seung‐Ki Kwok","orcid":"0000-0002-6142-8364","position":10,"is_corresponding":false},{"id":821762,"name":"Joon Young Hyon","orcid":"0000-0003-3620-1536","position":11,"is_corresponding":false},{"id":296097,"name":"Seunghee Cha","orcid":"0000-0003-3772-1832","position":12,"is_corresponding":false},{"id":676687,"name":"Yun Jong Lee","orcid":"0000-0001-7615-8611","position":13,"is_corresponding":false},{"id":472734,"name":"Sung Gap Im","orcid":"0000-0002-2802-6398","position":14,"is_corresponding":false},{"id":676688,"name":"Yoosik Kim","orcid":"0000-0003-3064-4643","position":15,"is_corresponding":false},{"id":821757,"name":"Jimin Yoon","orcid":"0000-0002-7010-082X","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-19T00:22:51.435773Z","pmid":"36284513","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}