Persistent interferon signaling causes sensory neuron plasticity and pain before and during arthritis

Although inflammatory processes in rheumatoid arthritis have been described, mechanisms driving pain are poorly defined. Here, we used a multitude of approaches to uncover the neural basis and causes of inflammatory pain. We show in mice with cartilage autoantibody-induced arthritis that early immune activation and a cytokine storm were mainly driven by vascular cells and monocytes/macrophages in the dorsal root ganglion. However, persistently elevated interferons and receptor activation of the MNK1/MNK2-eIF4E signaling pathway at all disease phases caused sensory-motor dysfunction and pain by inducing hyperexcitability and sensitization of a GFRA3+ C-fiber subtype of joint-innervating sensory neurons. Signaling pathway inhibition in vivo reversed pain and restored limb function. Like mice, human sensory neurons expressed interferon receptors, and type 1 interferons and signaling were increased only in individuals with painful rheumatoid arthritis. The finding that joint pain before and during arthritis is caused by a defined cytokine and signaling pathway holds promise for targeted therapies for pain relief in arthritis.