Neuronal FcγRI mediates acute and chronic joint pain
Li Wang, … , Michael J. Caterina, Lintao Qu
Li Wang, … , Michael J. Caterina, Lintao Qu
Published September 3, 2019; First published June 18, 2019
Citation Information: J Clin Invest. 2019;129(9):3754-3769. https://doi.org/10.1172/JCI128010.
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Research Article Neuroscience

Neuronal FcγRI mediates acute and chronic joint pain

Abstract

Although joint pain in rheumatoid arthritis (RA) is conventionally thought to result from inflammation, arthritis pain and joint inflammation are at least partially uncoupled. This suggests that additional pain mechanisms in RA remain to be explored. Here we show that FcγRI, an immune receptor for IgG immune complex (IgG-IC), is expressed in a subpopulation of joint sensory neurons and that, under naive conditions, FcγRI cross-linking by IgG-IC directly activates the somata and peripheral terminals of these neurons to evoke acute joint hypernociception without obvious concurrent joint inflammation. These effects were diminished in both global and sensory neuron–specific Fcgr1-knockout mice. In murine models of inflammatory arthritis, FcγRI signaling was upregulated in joint sensory neurons. Acute blockade or global genetic deletion of Fcgr1 significantly attenuated arthritis pain and hyperactivity of joint sensory neurons without measurably altering joint inflammation. Conditional deletion of Fcgr1 in sensory neurons produced similar analgesic effects in these models. We therefore suggest that FcγRI expressed in sensory neurons contributes to arthritis pain independently of its functions in inflammatory cells. These findings expand our understanding of the immunosensory capabilities of sensory neurons and imply that neuronal FcγRI merits consideration as a target for treating RA pain.

Authors

Li Wang, Xiaohua Jiang, Qin Zheng, Sang-Min Jeon, Tiane Chen, Yan Liu, Heather Kulaga, Randall Reed, Xinzhong Dong, Michael J. Caterina, Lintao Qu

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Figure 4

FcγRI mediates IgG-IC–induced acute joint nocifensive behaviors in mice.

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FcγRI mediates IgG-IC–induced acute joint nocifensive behaviors in mice....
(A–C) Comparison of basal mechanical sensitivity to ankle press (A) and to plantar stimulation with von Frey filaments (B), and basal thermal sensitivity to plantar application of radiant heat (C), between Fcgr1+/+ (n = 9 mice) and global Fcgr1–/– mice (n = 12 mice). P > 0.05; unpaired Student’s t test or 2-way ANOVA for repeated measures followed by Bonferroni’s post hoc test. (D–F) Global Fcgr1–/– mice (n = 12 mice) exhibited a higher mechanical threshold in the ankle (D) and lower paw withdrawal frequency (PWF) to 0.07 (E) and 0.4 g force (F) applied to the hind paw following i.a. injection of IgG-IC (100 μg/mL; 10 μL) compared with Fcgr1+/+ control littermates (n = 9 mice). *P < 0.05 vs. Fcgr1+/+ controls, #P < 0.05 vs. before injection; 2-way ANOVA for repeated measures followed by Bonferroni’s post hoc test. (G and H) Depletion of synovial macrophages with liposomal clodronate (5 mg/mL; 6 μL) had no significant effects on mechanical hyperalgesia in the ankle (G) or hind paw (H) in mice upon injection of IgG-IC, compared with liposomal control (Veh). n = 10 mice per group; P > 0.05; 2-way ANOVA for repeated measures followed by Bonferroni’s post hoc test. (I–L) No significant differences were seen in IgG-IC–induced mechanical hyperalgesia in the ankle and hind paw in mice lacking T cells (Rag1–/–) or mast cells (c-KitW-sh/W-sh) compared with WT controls. n = 10–11 mice per group; P > 0.05; 2-way ANOVA for repeated measures followed by Bonferroni’s post hoc test.