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

Abstract

Chronic or episodic joint pain is a major symptom in rheumatoid arthritis (RA) and its adequate treatment represents an unmet medical need. However, the cellular and molecular mechanisms underlying RA pain remain elusive. Non-coding microRNAs (miRNAs) have been implicated in the pathogenesis of RA as negative regulators of the stability or translation 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 in a mouse model of collagen II-induced arthritis (CIA). Moreover, this effect was likely mediated, at least in part, by Fc{gamma}RI since miR-544-3p mimic downregulated Fc{gamma}RI in the DRG during arthritis and genetic deletion of Fc{gamma}RI produced similar antihyperalgesic effects in the CIA model. This notion was further supported by a dual luciferase assay showing that miR-544-3p targeted Fc{gamma}RI by directly binding to its 3UTR. In addition, Fc{gamma}RI expression in DRG neurons in vitro was downregulated by miR-544-3p mimic and upregulated by miR-544-3p inhibitor. In naive mice, miR-544-3p mimic alleviated acute joint pain hypersensitivity induced by IgG immune complex (IgG-IC), whereas miR-544-3p inhibitor potentiated the pro-nociceptive behavioral effect of IgG-IC. 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.