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.

Automated summary

The study elucidates a molecular mechanism linking TNF to type-I interferon signaling, demonstrating that TNF triggers a cGAS-STING-dependent interferon response and inhibits PINK1-mediated mitophagy. This leads to altered mitochondrial function, increased cytosolic mtDNA levels, and a transcriptional response that mimics macrophages from rheumatoid arthritis patients. Additionally, in an inflammatory arthritis mouse model, cGAS deficiency blocked interferon responses and reduced inflammatory cell infiltration and joint swelling. Therapeutic targeting of cGAS/STING in TNF-driven diseases may offer potential benefits.