Mitochondrial damage and activation of innate immunity in salivary gland cells. Sjögren’s syndrome (SS) is a chronic, autoimmune disorder affecting almost all organ systems, including the exocrine glands, nervous system, joints, lungs, and the gastrointestinal tract. SS disproportionately affects women (9:1 ratio), and unlike other autoimmune disorders, SS patients are older, typically diagnosed between 40-60 years of age, and show evidence for increased oxidative stress.
Recent literature shows that increased oxidative stress causes mitochondrial dysfunction, leading to the release of mitochondrial DNA (mtDNA) into the cytosol. This mtDNA is recognized as a danger signal, and it induces type I IFN and pro-inflammatory cytokines through the cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes (STING) protein-interferon regulatory factor 3 (IRF3) axis. Furthermore, the activation of the cGAS-STING-IRF3 axis also causes cellular senescence, contributing to the adverse effects of aging.
Despite the evidence for oxidative stress and elevated type I IFN response, the role of mtDNA in the activation of innate immunity in SS is not known. Therefore, our laboratory has generated in vitro and in vivo genetic models for inducing mitochondrial damage in mouse salivary glands. These model systems are being used to investigate the role of oxidative stress and excessive activation of innate immunity in the development of SS.