Elevated level of mitochondrial RNAs contributes to the molecular characteristics of Sjögren’s syndrome

Abstract

Sjӧgren’s syndrome (SS) is a systemic autoimmune disease that attacks exocrine organs and leads to chronic inflammation with decreased tear and saliva production. Despite the extensive dryness and other complications, it is underdiagnosed, undertreated, and under-researched. Particularly, there exists no pathophysiological marker that may allow earlier diagnosis and capture the progression of the disease. Here, we investigate the role of cellular double-stranded RNAs, especially those from mitochondria (mt-dsRNAs) in SS. We find that mt-dsRNA expressions were elevated in saliva and tear of SS patients, but not in non-SS sicca patients. We then establish a functional polymer film-based surface modification to establish an in vitro 3-D culture system of human salivary gland acinar cells and analyze the role of mt-dsRNAs in response to exogenous dsRNA stress. We find that dsRNA stress leads to increased expression of mt-dsRNAs and their cytosolic export, which is accompanied by molecular phenotypes of SS such as increased type I interferons, decreased tight junction complex proteins, and decreased water channel protein Aquaporin-5. Interestingly, reducing mt-dsRNA expression by inhibiting mitochondrial RNA polymerase rescued the molecular phenotypes of SS induced by dsRNA stress. Moreover, antioxidant resveratrol alleviates the effect of dsRNA stress partly by preventing mt-dsRNA induction. Altogether, our study unveils mt-dsRNAs as a potential pathophysiological marker and therapeutic target to prevent SS and other autoimmune disorders.