Neuronal FcγRI mediates acute and chronic joint pain
Li Wang, … , Michael J. Caterina, Lintao Qu
Li Wang, … , Michael J. Caterina, Lintao Qu
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 10

FcγRI contributes to hyperactivity of joint sensory neurons following AIA.

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FcγRI contributes to hyperactivity of joint sensory neurons following AI...
(A and B) Distribution of the recorded C (A) and Aδ (B) fibers innervating the ankle of Fcgr1+/+ and Fcgr1–/– mice 1 day after vehicle control (Ctrl) or mBSA (AIA) challenge. No significant difference in CV was seen between treatments or genotypes. P > 0.05, 2-way ANOVA followed by Bonferroni’s post hoc test. (C) Representative traces of abnormal spontaneous activity (SA) were recorded in DiI-labeled joint sensory neurons of mice. (D) Global Fcgr1–/– mice exhibited lower incidence of SA at day 1 after AIA. *P < 0.05 vs. controls, #P < 0.05 vs. Fcgr1+/+ mice; χ2 test. Number of neurons tested is noted above graphs. (E) Responses of joint sensory neurons in Fcgr1+/+ and Fcgr1–/– mice to a 2-second, 10-mN mechanical stimulus delivered via a 100-μm probe in control (Ctrl) and AIA mice. (F) Prevalence of mechanically evoked after-discharges in joint sensory neurons of Fcgr1+/+ and Fcgr1–/– mice on day 1 after challenge. *P < 0.05 vs. controls, #P < 0.05 vs. Fcgr1+/+ mice; χ2 test. Number of neurons tested is noted above graphs. (G) Representative responses of joint sensory neurons in Fcgr1+/+ and Fcgr1–/– mice to mechanical stimulation (2 seconds in duration) of their RF with von Frey filaments (100 μm tip diameter) at the indicated bending forces on day 1 after challenge. (H) The mean number of action potentials evoked by mechanical stimuli in joint sensory neurons from Fcgr1+/+ (Ctrl: 29 neurons; AIA: 23 neurons) and Fcgr1–/– mice (Ctrl: 21 neurons; AIA: 25 neurons) on day 1 after AIA. *P < 0.05, **P < 0.01 vs. controls; #P < 0.05, ##P < 0.01 vs. Fcgr1+/+; 2-way repeated-measures ANOVA followed by Bonferroni’s post hoc test.