Autoantibody-induced arthritis pain caused by a sustained type I interferon signaling

Pain in rheumatoid arthritis is highly debilitating, impacts quality of life and lacks adequate treatment options. Although the presence of pathogenic autoantibodies and systemic and joint inflammation are distinctive features of the disease, the molecular and neuronal basis of pain remains unclear. Here, we identify the molecular mechanism and causative neurons for autoantibody-induced pain in mice. Single-cell RNA sequencing analysis during arthritis pain revealed interferon-stimulated genes, with a persistent nociceptor neuron sensitization, local inflammation and a causative role of interferons acting on polymodal GFRa3-positive C-fiber-nociceptors, as the origin of pain. Consistently, interferon inhibition blocked gene expression alterations and prevented onset as well as reversed established and residual arthritis pain. The discovered pain-causative mechanism may represent a novel therapeutic approach for treatment of pain in rheumatoid arthritis. Overall design: Mouse dorsal root ganglion cells isolated at different timepoints after induction of experimental arthritis and analyzed using scRNA-seq