한빛사논문
- 조회406
Jimin Yoon,1,14 Minseok Lee,1,14 Ahsan Ausaf Ali,1 Ye Rim Oh,2 Yong Seok Choi,2 Sujin Kim,1 Namseok Lee,1 Se Gwang Jang,3 Seonghyeon Park,1 Jin-Haeng Chung,4 Seung-Ki Kwok,5 Joon Young Hyon,6 Seunghee Cha,7* Yun Jong Lee,8,9* Sung Gap Im,1,10* and Yoosik Kim1,11,12,13*
1Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea; 2Medical Science Research Institute, Seoul National University Bundang Hospital, Seongnam 13620, Republic of Korea; 3The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; 4Department of Pathology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; 5Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; 6Department of Ophthalmology, Seoul National University Bundang Hospital, Seongnam 13620, Republic of Korea; 7Department of Oral and Maxillofacial Diagnostic Sciences, University of Florida College of Dentistry, Gainesville, FL 32610, USA; 8Division of Rheumatology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam 13620, Republic of Korea; 9Department of Internal Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; 10KAIST Institute for NanoCentury (KINC), KAIST, Daejeon 34141, Republic of Korea; 11KAIST Institute for Health Science and Technology (KIHST), KAIST, Daejeon 34141, Republic of Korea; 12KAIST Institute for BioCentury (KIB), KAIST, Daejeon, 34141, Republic of Korea; 13BioProcess Engineering Research Center and BioInformatics Research Center, KAIST, Daejeon, 34141, Republic of Korea
14These authors contributed equally
*Corresponding author.
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 tear of SS patients (n=73 for saliva and n=16 for tear) 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 JAK1/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. Lastly, 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.
논문정보
- Research article
- 2022년 12월 (BRIC 등록일 2022-10-14)
- 국내(교신)+국외 연구진
- 생명과학 > 분자생물학
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