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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Categories: 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 5

Neuronal FcγRI contributes to IgG-IC–induced acute nocifensive behaviors.

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Neuronal FcγRI contributes to IgG-IC–induced acute nocifensive behaviors...
(A) Strategy for generation of primary sensory neuron–selective Fcgr1-knockout mice. Two loxP sites were inserted 5′ to exon 1 and 3′ to exon 3 of the Fcgr1 gene, respectively. Primers UF and UR and primers 3-4F and 3-4R, respectively, were used to confirm correct loxP insertions at each site. Deletion of the Fcgr1 gene in primary sensory neurons was achieved by crossing of Fcgr1fl/fl mice with PirtCre mice. (B) RT-qPCR analysis using primers 1F and 3R from A revealed a significant reduction in Fcgr1 mRNA expression in DRG tissue (n = 10–11 mice per group) but not in spleen of PirtCre Fcgr1fl/fl mice (n = 4–5 mice per group) compared with Fcgr1fl/fl controls. (C) Representative ISH image of DRG and spleen. Scale bar: 50 μm. Inset shows area of high-power magnification; scale bar: 20 μm. Quantification shows reductions in Fcgr1 mRNA expression in DRG neurons (NeuN) but not in spleen macrophages (F4/80) of PirtCre Fcgr1fl/fl mice compared with Fcgr1fl/fl controls. n = 4 mice per group; *P < 0.05 vs. Fcgr1fl/fl controls. For B and C, unpaired Student’s t test was used. (D–F) No significant differences were observed between genotypes in basal mechanical sensitivity in the ankle (D) or hind paw (E), or in basal thermal sensitivity in the hind paw (F). n = 10–19 mice per group; P > 0.05; unpaired Student’s t test or 2-way ANOVA for repeated measures followed by Bonferroni’s post hoc test. (G–I) Time course of mechanical threshold in the ankle and paw withdrawal frequency (PWF) to 0.07 and 0.4 g force before and after i.a. injection of IgG-IC (100 μg/mL; 10 μL). n = 9 mice per group; *P < 0.05 vs. Fcgr1fl/fl controls; #P < 0.05, ##P < 0.01 vs. before injection; 2-way ANOVA for repeated measures followed by Bonferroni’s post hoc test.