Mitochondrial double-stranded RNAs as a pivotal mediator in the pathogenesis of Sjӧgren’s syndrome

Cited 0 time in Web of Science Cited 1 time in Scopus

Yoon, Jimin; Lee, Minseok; Ali, Ahsan Ausaf; Oh, Ye Rim; Choi, Yong Seok; Kim, Sujin; Lee, Namseok; Jang, Se Gwang; Park, Seonghyeon; Chung, Jin-Haeng; Kwok, Seung-Ki; Hyon, Joon Young; Cha, Seunghee; Lee, Yun Jong; Im, Sung Gap; Kim, Yoosik

Issue Date
Nature Publishing Group
Molecular Therapy - Nucleic Acids, Vol.30, pp.257-269
Sjogren'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 increas-ingly recognized as pivotal mediators in SS, but their endoge-nous 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 hu-man salivary gland cells, we show that stimulation by exoge-nous 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 auto -immune characteristics by preventing mt-dsRNA-mediated immune activation. Last, direct suppression of mt-dsRNAs re-verses 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.
Files in This Item:
There are no files associated with this item.
Appears in Collections:
College of Medicine/School of Medicine (의과대학/대학원)Dept. of Medicine (의학과)Journal Papers (저널논문_의학과)
College of Medicine/School of Medicine (의과대학/대학원)Dept. of Medicine (의학과)Journal Papers (저널논문_의학과)
  • mendeley

Items in S-Space are protected by copyright, with all rights reserved, unless otherwise indicated.