Fcγ Receptor I–Coupled Signaling in Peripheral Nociceptors Mediates Joint Pain in a Rat Model of Rheumatoid Arthritis

Abstract

Objective. Rheumatoid arthritis (RA) is often accompanied by joint pain and inflammation. Previous studies have demonstrated that functional Fcγ receptor I (FcγRI) is expressed in dorsal root ganglion (DRG) neurons and might contribute to pain in rodent models of antigen-induced arthritis (AIA). This study was undertaken to elucidate the roles of nociceptive neuronal FcγRI-coupled signaling in the development of joint pain in AIA. Methods. RNA sequencing was used to investigate the transcriptome profile changes in the DRG in a rat model of AIA. A primary sensory neuron-specific Fcgr1a conditional-knockout (CKO) rat was established by crossing rats carrying a loxP-flanked Fcgr1a with a Pirt-specific Cre line. Behavioral, morphologic, and molecular studies were conducted to evaluate the differences between wild-type (WT) and CKO rats after AIA. Results. We first showed that AIA induced a transcriptome profile change in the DRG, involving a number of key proteins downstream of the FcγRI-related signaling pathway. Compared to the WT rats, both the IgG immune complex-induced acute pain and AIA-induced pain were alleviated in CKO rats. Moreover, the AIA-induced activation of FcγRI-related signaling in DRGs was significantly reduced in CKO rats. In addition, CKO rats showed attenuated joint swelling after AIA. Conclusion. These results indicate that activation of FcγRI-coupled signaling in DRG neurons plays an important role in the development of joint pain in AIA. Our findings may provide novel insights into the interactions between the peripheral nervous system and the immune system in pathologic conditions and might suggest potential biotargets for the treatment of pain in RA.

Sensory Neuron Expressed FcγRI Mediates Postinflammatory Arthritis Pain in Female Mice

“…Our previous work has demonstrated the contribution of FcγRI to arthritis pain in several murine models of inflammatory arthritis ( 14 , 16 ). We and other groups have reported that FcγRI is also present in primary sensory neurons besides immune cells ( 13 , 24 , 25 ). Moreover, we showed that neuronally expressed FcγRI mediated the sensitization of joint nociceptors and arthritis pain during inflammation in animal models of RA through a mechanism independent of inflammation ( 14 ).…”

miR-544-3p mediates arthritis pain through regulation of FcγRI

“…In addition to immune cells, we and other groups have identified that FcγRI is also expressed in primary sensory neurons 25,26,44,45 . Moreover, our recent study showed that neuronally expressed FcγRI mediated hyperactivity of joint sensory neurons and arthrits pain in animal models of RA through a mechanism independent of inflammation 26 .…”

Targeting the High Affinity Receptor, FcγRI, in Autoimmune Disease, Neuropathy, and Cancer

“…Hence, IgG-IC accumulation in the inflamed joint is sufficient to directly stimulate and sensitize joint sensory neurons through neuronal FcγRI, resulting in joint pain. Direct FcγRI blockade with neutralizing antibodies and FcγRI genetic knockout substantially reduced pain-related behaviors in the AIA mouse model [75,76]. These findings suggest that FcγRI can contribute to arthritis pain through a non-inflammatory mechanism, making it a promising therapeutic target in RA patients with pain refractory to current anti-inflammatory treatments (Figure 3.6).…”

“…IgG-IC/FcγRI signaling has been linked to both the pathogenesis [54,73,81] and disease-associated pain [8,75,76] in RA. Joint pain is a prominent clinical characteristic of RA, which is caused in part by synovitis and joint destruction [94].…”

“…Moreover, in various autoimmune diseases, antigens and autoantibodies crosslink and form ICs that bind and activate FcγRI [55]. These inflammatory effector functions can cause extensive tissue damage in diseases like RA and SLE, but also chronic joint pain [75,76]. In these autoimmune diseases, blocking IC-FcγRI interactions with mAbs that specifically block the ligand binding domain of FcγRI may be beneficial.…”