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

Abstract

Chronic joint pain is a major symptom in rheumatoid arthritis (RA) and its adequate treatment represents an unmet medical need. Noncoding microRNAs (miRNAs) have been implicated in the pathogenesis of RA as negative regulators of specific target mRNAs. Yet, their significance in RA pain is still not well defined. We and other groups recently identified neuronally expressed Fc gamma RI as a key driver of arthritis pain in mouse RA models. Thus, we tested the hypothesis that miRNAs that target and regulate neuronal Fc gamma RI attenuate RA pain. Here, we show that miR-544-3p was robustly downregulated, whereas Fc gamma RI was significantly upregulated in the dorsal root ganglion (DRG) in mouse RA models. Intrathecal injection of miR-544-3p mimic attenuated established mechanical and heat hyperalgesia partly through the downregulation of Fc gamma RI in the DRG in a mouse model of collagen II-induced arthritis. Moreover, this effect was likely mediated, at least in part, by Fc gamma RI because miR-544-3p mimic downregulated Fcgr1 mRNA expression in the DRG during arthritis and genetic deletion of Fcgr1 produced similar antihyperalgesic effects in the collagen II-induced arthritis model. This notion was further supported by a dual luciferase assay showing that miR-544-3p directly targeted Fcgr1 3'UTR. In naive mice, miR-544-3p mediated acute joint pain hypersensitivity induced by IgG immune complex through the regulation of Fc gamma RI. These findings suggest that miR-544-3p causally participates in the maintenance of arthritis pain by targeting neuronal Fc gamma RI, and thus define miR-544-3p as a new potential therapeutic target for treating RA pain.