Neuronal FcγRI mediates acute and chronic joint pain
Li Wang, Xiaohua Jiang, Qin Zheng, Sang-Min Jeon, Tiane Chen, Yan Liu, Heather Kulaga, Randall Reed, Xinzhong Dong, Michael J. Caterina, Lintao Qu
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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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 2

IgG-IC directly activates joint sensory neurons through FcγRI in vitro and in vivo.

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IgG-IC directly activates joint sensory neurons through FcγRI in vitro a...
(A) Representative traces of Ca2+ responses evoked by antigen (Ag) alone (BSA), IgG-IC (1 μg/mL, 2 minutes), and capsaicin (CAP; 1 μM, 10 seconds) in joint-innervating (DiI-labeled) DRG neurons from Fcgr1+/+ (left) and global Fcgr1–/– (right) mice. (B) Quantitative analysis showed that IgG-IC, but not Ag or antibody (Ab; anti-BSA) alone, evoked Ca2+ responses in a larger proportion of DiI-labeled joint sensory neurons from Fcgr1+/+ mice than those from Fcgr1–/– mice. *P < 0.05 vs. Fcgr1+/+, #P < 0.05 vs. Ag; χ2 test. Number of responsive neurons and total number tested are in parentheses. (C) Left: Representative DiI fluorescence (red) in L4 DRG neuronal cell bodies in PirtCre-GCamp6 mice that were either Fcgr1+/+ or Fcgr1–/–, retrogradely labeled with ankle joint injection of DiI (2 mg/mL; 8 μL in saline). Right: GCAMP6 fluorescence (green) in the same fields before and after stimulation of the RF with the indicated stimuli. White arrows show DRG neurons from Fcgr1+/+ mice exhibiting an increase in GCAMP6 fluorescence when the ankle was squeezed with blunt forceps and 4 minutes after IgG-IC (100 μg/mL; 10 μL) was injected into ankle joint cavity, but not after vehicle (PBS; 10 μL) or monomeric IgG (100 μg/mL; 10 μL) was injected. By contrast, little or no increase in GCAMP6 fluorescence was induced by IgG-IC in joint sensory neurons from Fcgr1–/– mice. Scale bar: 50 μm. (D) Quantitative analysis of Ca2+ responses to PBS (n = 6 mice), monomeric IgG (n = 6 mice), and IgG-IC (n = 10 mice) in joint sensory neurons of Fcgr1+/+ mice and IgG-IC in Fcgr1–/– mice (n = 8 mice). *P < 0.05 vs. Fcgr1+/+, #P < 0.01 vs. PBS; 1-way ANOVA followed by Tukey’s test.