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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

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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 9

Acute pharmacological blockade of FcγRI attenuates AIA-associated pain in male mice.

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Acute pharmacological blockade of FcγRI attenuates AIA-associated pain i...
(A) Experimental schematic indicating once-daily injection of anti-CD64 (2.25 μg; 5 μL) or IgG2b isotype control (2.25 μg; 5 μL) into knee (for histology) or ankle cavity (for behavioral testing) of mice on days 1 and 2 after AIA. Pain-related behaviors were measured within 3 hours after each injection. (B–F) Effects of repeated daily i.a. injection of anti-CD64 or IgG2b isotype control on mechanical threshold in the ankle (B), paw withdrawal frequency (PWF) in response to 0.07 g (C) and 0.4 g force (D), paw withdraw latency to radiant heat (E), and ankle joint diameter (F) in the mice with AIA. n = 9 mice per group; *P < 0.05 vs. control IgG2b isotype, #P < 0.05 vs. day 0; 2-way ANOVA for repeated measures followed by Bonferroni’s post hoc test. (G) H&E staining assessment of synovitis in the inflamed knee joint of AIA mice treated with IgG2b isotype control (n = 5 mice) or anti-CD64 (n = 6 mice). S, synovium. Scale bar: 100 μm. (H) Quantification showed no difference in synovitis score between treatment groups. P > 0.05, unpaired Student’s t test.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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