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.
Su et al. (2026) studied this question.