Targeting mitochondrial double-stranded RNAs ameliorates autoimmune characteristics of Sjogren’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 (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 type I IFN response in SS. We find that mt-dsRNAs are elevated in the saliva and tear of SS patients as well as in salivary glands of non-obese diabetic mice with salivary dysfunction. In line with this, elevated expressions of mt-dsRNAs are associated with exocrine dysfunction and glandular lymphocytic infiltration from SS patients. Using the in-house-developed 3D culture, we show that dsRNA stimulation increases mt-dsRNAs expression via JAK1/STAT pathway and facilitates their cytosolic export, which is accompanied by autoimmune signatures observed in SS. We further show that muscarinic receptor ligand acetylcholine ameliorates autoimmune characteristics by preventing mt-dsRNA-mediated antiviral signaling. Lastly, we find that hindering mt-dsRNA induction or direct suppression of mt-dsRNA expression via treatment of 2-C′-methyladenosine (2-CM), an inhibitor of mitochondrial RNA polymerase (POLRMT), reverses the autoimmune signatures of SS. Altogether, our study underscores the significance of mt-dsRNA upregulation in exacerbating aberrant immune activation driving autoimmune diseases such as SS.