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 FcγRI as a key driver of arthritis pain in mouse RA models. Thus, we tested the hypothesis that miRNAs that target and regulate neuronal FcγRI attenuate RA pain. Here, we show that miR-544-3p was robustly downregulated, whereas FcγRI 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 FcγRI in the DRG in a mouse model of collagen II–induced arthritis. Moreover, this effect was likely mediated, at least in part, by FcγRI 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 naïve mice, miR-544-3p mediated acute joint pain hypersensitivity induced by IgG immune complex through the regulation of FcγRI. These findings suggest that miR-544-3p causally participates in the maintenance of arthritis pain by targeting neuronal FcγRI, and thus define miR-544-3p as a new potential therapeutic target for treating RA pain.

慢性关节疼痛是类风湿性关节炎（RA）的主要症状，其充分的治疗代表了未满足的医疗需求。非编码 microRNA (miRNA) 作为特定靶标 mRNA 的负调节因子参与 RA 的发病机制。然而，它们在 RA 疼痛中的重要性仍未明确。我们和其他小组最近发现神经元表达的 FcγRI 是小鼠 RA 模型中关节炎疼痛的关键驱动因素。因此，我们测试了这样的假设：靶向和调节神经元 FcγRI 的 miRNA 可减轻 RA 疼痛。在这里，我们发现，在小鼠 RA 模型的背根神经节 (DRG) 中，miR-544-3p 显着下调，而 FcγRI 显着上调。在 II 型胶原诱导的关节炎小鼠模型中，鞘内注射 miR-544-3p 模拟物可部分通过下调 DRG 中的 FcγRI 来减弱已建立的机械和热痛觉过敏。此外，这种效应可能至少部分是由 FcγRI 介导的，因为 miR-544-3p 模拟物在关节炎期间下调 DRG 中Fcgr1 mRNA 的表达，而Fcgr1的基因缺失在 II 型胶原诱导的关节炎模型中产生了类似的抗痛觉过敏作用。双荧光素酶测定进一步支持了这一观点，该测定显示 miR-544-3p 直接靶向Fcgr1 3'UTR。在首次实验的小鼠中，miR-544-3p 通过调节 FcγRI 介导 IgG 免疫复合物诱导的急性关节疼痛超敏反应。这些发现表明，miR-544-3p 通过靶向神经元 FcγRI 因果性地参与关节炎疼痛的维持，从而将 miR-544-3p 定义为治疗 RA 疼痛的新的潜在治疗靶点。