Janus kinase (JAK) inhibitors, such as baricitinib, are widely used to treat rheumatoid arthritis (RA). Clinical studies show that baricitinib is more effective at reducing pain than other similar drugs. Here, we aimed to elucidate the molecular mechanisms underlying the pain relief conferred by baricitinib, using a mouse model of arthritis. We treated collagen antibody-induced arthritis (CAIA) model mice with baricitinib, celecoxib, or vehicle, and evaluated the severity of arthritis, histological findings of the spinal cord, and pain-related behaviours. We also conducted RNA sequencing (RNA-seq) to identify alterations in gene expression in the dorsal root ganglion (DRG) following baricitinib treatment. Finally, we conducted in vitro experiments to investigate the direct effects of baricitinib on neuronal cells. Both baricitinib and celecoxib significantly decreased CAIA and improved arthritis-dependent grip-strength deficit, while only baricitinib notably suppressed residual tactile allodynia as determined by the von Frey test. CAIA induction of inflammatory cytokines in ankle synovium, including interleukin (IL)-1β and IL-6, was suppressed by treatment with either baricitinib or celecoxib. In contrast, RNA-seq analysis of the DRG revealed that baricitinib, but not celecoxib, restored gene expression alterations induced by CAIA to the control condition. Among many pathways changed by CAIA and baricitinib treatment, the interferon-alpha/gamma, JAK-signal transducer and activator of transcription 3 (STAT3), and nuclear factor kappa B (NF-κB) pathways were considerably decreased in the baricitinib group compared with the celecoxib group. Notably, only baricitinib decreased the expression of colony-stimulating factor 1 (CSF-1), a potent cytokine that causes neuropathic pain through activation of the microglia–astrocyte axis in the spinal cord. Accordingly, baricitinib prevented increases in microglia and astrocytes caused by CAIA. Baricitinib also suppressed JAK/STAT3 pathway activity and Csf1 expression in cultured neuronal cells. Our findings demonstrate the effects baricitinib has on the DRG in relation to ameliorating both inflammatory and neuropathic pain.

中文翻译：

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Baricitinib 通过调节背根神经节神经元中的 IL-6/JAK/STAT3 通路和 CSF-1 表达来改善胶原抗体诱导的关节炎小鼠的炎症和神经性疼痛


Janus激酶（JAK）抑制剂，例如巴瑞替尼（baricitinib），广泛用于治疗类风湿性关节炎（RA）。临床研究表明，巴瑞克替尼比其他类似药物在减轻疼痛方面更有效。在这里，我们的目的是使用关节炎小鼠模型来阐明巴瑞替尼缓解疼痛的分子机制。我们用巴瑞替尼、塞来昔布或载体治疗胶原抗体诱导的关节炎 (CAIA) 模型小鼠，并评估关节炎的严重程度、脊髓的组织学发现和疼痛相关行为。我们还进行了 RNA 测序 (RNA-seq)，以确定巴瑞替尼治疗后背根神经节 (DRG) 基因表达的变化。最后，我们进行了体外实验来研究巴瑞替尼对神经元细胞的直接影响。巴瑞克替尼和塞来昔布均显着降低 CAIA 并改善关节炎依赖性握力缺陷，而根据冯弗雷试验确定，只有巴瑞克替尼显着抑制残余触觉异常性疼痛。巴瑞克替尼或塞来昔布治疗可抑制 CAIA 在踝关节滑膜中诱导炎症细胞因子，包括白细胞介素 (IL)-1β 和 IL-6。相比之下，DRG 的 RNA-seq 分析表明，巴瑞替尼（而不是塞来昔布）将 CAIA 诱导的基因表达改变恢复到对照条件。在 CAIA 和巴瑞替尼治疗改变的许多通路中，与巴瑞替尼组相比，干扰素 α/γ、JAK 信号转导器和转录激活子 3 (STAT3) 以及核因子 κ B (NF-κB) 通路显着减少塞来昔布组。 值得注意的是，只有巴瑞克替尼降低了集落刺激因子 1 (CSF-1) 的表达，这是一种有效的细胞因子，通过激活脊髓中的小胶质细胞-星形胶质细胞轴引起神经性疼痛。因此，巴瑞克替尼可以预防由 CAIA 引起的小胶质细胞和星形胶质细胞的增加。 Baricitinib 还抑制培养神经元细胞中的 JAK/STAT3 通路活性和 Csf1 表达。我们的研究结果表明巴瑞替尼对 DRG 的影响与减轻炎症和神经性疼痛有关。