Laragione Teresina, Harris Carolyn, Rice Natasha, Gulko Percio S
Division of Rheumatology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
iScience. 2024 May 31;27(6):110158. doi: 10.1016/j.isci.2024.110158. eCollection 2024 Jun 21.
Receptor tyrosine kinases (RTKs) have an important role in arthritis severity and in models of rheumatoid arthritis (RA), but their regulation is not fully understood. The dual specificity phosphatase 6 (DUSP6) has been implicated in the regulation of RTK signaling, but never in the context of arthritis and autoimmunity. We used the KRN serum-induced arthritis (KSIA) model of RA and showed that DUSP6 mice were protected and had a 50% lower maximum arthritis score ( = 0.006) and reduced joint damage than C57BL/6 DUSP6+/+ controls. Serum levels of interleukin (IL) 10 were significantly increased (>2-fold), and IL6 decreased in DUSP6 mice. DUSP6 mice had increased numbers of IL10+ cells including Tr1 regulatory cells ( < 0.01). Introduction of the IL10 into DUSP6 (double knockout [KO]) reversed the DUSP6 protection. In conclusion, this study reports a pro-arthritic role for DUSP6. This discovery has the potential to generate a previously unknown target for therapies for RA and inflammatory diseases.
受体酪氨酸激酶（RTKs）在关节炎严重程度及类风湿关节炎（RA）模型中发挥重要作用，但其调节机制尚未完全明确。双特异性磷酸酶6（DUSP6）与RTK信号传导的调节有关，但从未在关节炎和自身免疫的背景下被研究过。我们利用RA的KRN血清诱导性关节炎（KSIA）模型，发现DUSP6基因敲除小鼠受到保护，其最大关节炎评分比C57BL/6 DUSP6+/+对照组低50%（P = 0.006），关节损伤也减少。DUSP6基因敲除小鼠的白细胞介素（IL）-10血清水平显著升高（>2倍），而IL-6水平降低。DUSP6基因敲除小鼠中包括Tr1调节性细胞在内的IL-10+细胞数量增加（P < 0.01）。将IL-10导入DUSP6基因双敲除（KO）小鼠可逆转DUSP6基因敲除小鼠的保护作用。总之，本研究报道了DUSP6在关节炎中的促炎作用。这一发现有可能为RA和炎症性疾病的治疗产生一个前所未知的靶点。
