(213) IgG-Immune Complex Directly Activates Joint Sensory Neurons through Neuronal FcγRI to Induce Arthritis Pain

Joint pain in rheumatoid arthritis (RA) represents a significant health burden. Although RA pain is conventionally thought to result from inflammation, it often persists even after control of inflammation with available therapies, suggesting the additional involvements of non-inflammatory mechanisms. Yet, such mechanisms remain largely unexplored. Our in situ hybridization assays suggested that the immune complex receptor FcγRI was expressed in a subpopulation of joint sensory neurons. Consistent with this finding, the proportion of joint sensory neurons exhibiting a Ca2+ increase in response to IgG-immune complex (IgG-IC), assayed both in vitro and in vivo, was lower in global FcγRI−/− mice, compared with wildtype mice. Injection of IgG-IC but not monomeric IgG into one ankle of naive mice evoked joint pain-related behaviors without concurrent joint swelling. This effect was diminished in global FcγRI−/− mice. Ablation of T and B cells, mast cells or macrophages had no effect on IgG-IC evoked nocifensive behaviors. Under arthritic conditions, FcγRI mRNA expression and function were upregulated in dorsal root ganglion (DRG) in a mouse model of antigen-induced arthritis (AIA). In vivo extracellular electrophysiological recordings on intact DRG showed that genetic deletion of FcγRI reduced the incidence of abnormal activity and mechanical hypersensitivity of joint sensory neurons in the context of AIA. Acute blockade of FcγRI with neutralizing antibody and genetic knockout of FcγRI significantly attenuated pain-related behaviors in the AIA model. Conversely, no significant differences between treatments or genotypes were observed in the inflamed joint in the expression level of cytokines or in immune cell infiltration. These findings indicate that FcγRI may contribute to arthritis pain through a non-inflammatory mechanism that parallels inflammation and joint damage and point towards a promising therapeutic target to consider for RA pain that is resistant to current anti-inflammatory treatments. Supported by NIAMS 1R01AR072230 to L.Q.