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

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, w...

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Main Authors: Jimin Yoon (Author), Minseok Lee (Author), Ahsan Ausaf Ali (Author), Ye Rim Oh (Author), Yong Seok Choi (Author), Sujin Kim (Author), Namseok Lee (Author), Se Gwang Jang (Author), Seonghyeon Park (Author), Jin-Haeng Chung (Author), Seung-Ki Kwok (Author), Joon Young Hyon (Author), Seunghee Cha (Author), Yun Jong Lee (Author), Sung Gap Im (Author), Yoosik Kim (Author)
Format: Book
Published: Elsevier, 2022-12-01T00:00:00Z.
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Summary: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.
Item Description:2162-2531
10.1016/j.omtn.2022.09.020

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