TNF leads to mtDNA release and cGAS/STING-dependent interferon responses that support inflammatory arthritis

Tumor necrosis factor (TNF) is a key driver of several inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis, in which affected tissues show an interferon-stimulated gene signature. Here, we demonstrate that TNF triggers a type-I interferon response that is dependent on the cyclic guanosine monophosphate-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. We show that TNF inhibits PINK1-mediated mitophagy and leads to altered mitochondrial function and to an increase in cytosolic mtDNA levels. Using cGAS-chromatin immunoprecipitation (ChIP), we demonstrate that cytosolic mtDNA binds to cGAS after TNF treatment. Furthermore, TNF induces a cGAS-STING-dependent transcriptional response that mimics that of macrophages from rheumatoid arthritis patients. Finally, in an inflammatory arthritis mouse model, cGAS deficiency blocked interferon responses and reduced inflammatory cell infiltration and joint swelling. These findings elucidate a molecular mechanism linking TNF to type-I interferon signaling and suggest a potential benefit for therapeutic targeting of cGAS/STING in TNF-driven diseases. [Display omitted] •Prolonged TNF treatment induces a cGAS/STING-dependent interferon response•TNF impacts mitochondrial function and blocks mitophagy•TNF leads to the release of mtDNA, which binds and activates cGAS•cGAS−/− mice are protected and prevent ISG induction in a K/BxN arthritis model Willemsen et al. show that prolonged TNF stimulation leads to interferon signaling in a cGAS/STING-dependent manner, where cGAS activation is triggered by cytosolic mtDNA. These findings establish a link between the appearance of interferon signatures in TNF-driven diseases and cGAS activation, which is shown in a relevant model of inflammatory arthritis.