Targeting mitochondrial double-stranded RNAs ameliorates autoimmune characteristics of Sjogrens syndrome

Sj[o]grens 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 and in salivary glands of non-obese diabetic mice with salivary dysfunction. 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 or antioxidant resveratrol ameliorates autoimmune characteristics by preventing mt-dsRNA- mediated immune activation. In addition, direct suppression of mt-dsRNAs reverses the autoimmune signatures of SS. Altogether, our study underscores the significance of mt-dsRNA upregulation and suggests mt-dsRNAs as an important key to the puzzle of SS. SummaryMitochondrial double-stranded RNA levels are elevated in the tear and saliva of SS patients. These RNAs promote type I interferon signature, as well as other autoimmune phenotypes in SS. Downregulation of mitochondrial dsRNAs alleviates autoimmune signatures of SS in salivary gland epithelial cells. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=128 SRC="FIGDIR/small/459934v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@16a5b2eorg.highwire.dtl.DTLVardef@1883e40org.highwire.dtl.DTLVardef@1aede96org.highwire.dtl.DTLVardef@197645c_HPS_FORMAT_FIGEXP M_FIG mt-dsRNAs as the molecular mediator of autoimmune phenotypes in SS. mt-dsRNAs are elevated in both human samples and mouse model of SS and function to exacerbate dsRNA-induced autoimmune phenotypes in SS. Countering the accumulation of mt- dsRNAs alleviates the autoimmune phenotypes in SGECs. C_FIG