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 3

IgG-IC elicits acute articular hypernociception in naive mice.

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IgG-IC elicits acute articular hypernociception in naive mice. (A–E) Mic...
(A–E) Mice were injected intra-articularly (i.a.) with IgG-IC (1, 10, 100 μg/mL; 10 μL), monomeric IgG (100 μg/mL; 10 μL), or vehicle (PBS; 10 μL), and pain-like behaviors and joint diameter were evaluated over 1–24 hours. Injection of IgG-IC, but not monomeric IgG, reduced mechanical threshold in the ankle (A) and increased the frequency of paw withdrawal in response to application of 0.07 and 0.4 g force via a von Frey filament (B and C), but did not induce heat hyperalgesia (D) or visible joint swelling (E) in the ipsilateral paw, compared with vehicle. n = 8–10 mice per group; *P < 0.05 vs. PBS, #P < 0.05 vs. before injection; 2-way ANOVA for repeated measures followed by Bonferroni’s post hoc test. PWF, paw withdrawal frequency; PWL, paw withdrawal latency. (F) Representative sections of knee joints taken 1 hour after i.a. injection with either PBS, monomeric IgG, or IgG-IC and stained for Ly6C/G, CD68, CD3, or c-Kit. S, synovium. Scale bar: 200 μm. (G) Quantification showed no significant differences between treatment groups. n = 4–5 mice per group; P > 0.05; 1-way ANOVA followed by Tukey’s test. (H) Representative sections of knee joint taken 1 hour after i.a. injection with PBS, monomeric IgG, or IgG-IC, stained with H&E, and scored for synovitis. S, synovium. Scale bar: 100 μm. No significant difference in synovitis score was observed between treatments. n = 3–4 mice per group; P > 0.05; 1-way ANOVA followed by Tukey’s test.