Dual-Specificity Phosphatase 5 Attenuates Autoimmune Arthritis in Mice via Reciprocal Regulation of the Th17/Treg Cell Balance and Inhibition of Osteoclastogenesis
Dual-Specificity Phosphatase 5 Attenuates Autoimmune Arthritis in Mice via Reciprocal Regulation of the Th17/Treg Cell Balance and Inhibition of Osteoclastogenesis
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DOI：
10.1002/art.38787
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发表时间：
2014-11-01
影响因子：
13.3
通讯作者：
Cho, Mi-La
中科院分区：
文献类型：
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作者：
Moon, Su-Jin;Lim, Mi-Ae;Cho, Mi-La
Objective.双特异性磷酸酶5（DUSP-5）是一种特异性地使MAPK的磷酸丝氨酸和磷酸酪氨酸残基两者去磷酸化的磷酸酶。MAPK的异常激活参与了类风湿关节炎的发病机制。本研究旨在研究DUSP-5在动物模型中预防自身免疫性关节炎发展的治疗潜力。用Ⅱ型胶原（CII）免疫DBA/1 J小鼠，诱导自身免疫性关节炎。CII免疫后8天，小鼠静脉注射pcDNA-DUSP 5或模拟载体，并进行电穿孔。酶联免疫吸附试验测定血清中抗CII抗体浓度。采用番红O、甲苯胺蓝和免疫组织化学染色对关节进行组织学分析。免疫组化染色和Western blotting分析转录因子的表达。流式细胞仪检测IL-17阳性的CD 4 + Th 17细胞和CD 4 + CD 25 + Foxp 3 + Treg细胞的比例。在DUSP 5过表达的小鼠中，关节炎的严重程度，如临床关节炎评分和组织学炎症和软骨损伤的程度所示，被减弱。注射pcDNA-DUSP 5的小鼠循环中总IgG和CII特异性IgG、IgG 1和IgG 2a水平较低。在DUSP 5处理组的脾脏中，Th 17细胞群体频率降低，Treg细胞频率增加。Th 17和Treg细胞在体内的相互调节与pSTAT-3和pERK活性的减弱以及pSTAT-5活性的增加有关。DUSP 5过表达通过下调破骨细胞生成分子来抑制关节损伤。结论。DUSP-5的抗关节炎特性与其对Th 17和Treg细胞的相互调节及其对ERK活性的抑制有关。
Objective. Dual-specificity phosphatase 5 (DUSP-5) is a phosphatase that specifically dephosphorylates both phosphoserine and phosphotyrosine residues of MAPK. The dysregulated activation of MAPK contributes to the pathogenesis of rheumatoid arthritis. This study was undertaken to investigate the therapeutic potential of DUSP-5 in preventing the development of autoimmune arthritis in an animal model.Methods. Autoimmune arthritis was induced in DBA/1J mice by immunization with type II collagen (CII). Eight days after CII immunization, the mice were injected intravenously with pcDNA-DUSP5 or mock vector, and electroporation was performed. The serum concentration of anti-CII antibodies was measured by enzyme-linked immunosorbent assay. Histologic analysis of the joints was performed using Safranin O, toluidine blue, and immunohistochemical staining. The expression of transcription factors was analyzed by immunostaining and Western blotting. The frequencies of interleukin-17-producing CD4+ Th17 cells and CD4+CD25+Foxp3+ Treg cells were analyzed by flow cytometry.Results. In DUSP5-overexpressing mice, the severity of arthritis, as indicated by the clinical arthritis score and the extent of histologic inflammation and cartilage damage, was attenuated. The pcDNA-DUSP5-injected mice had lower circulating levels of total and CII-specific IgG, IgG1, and IgG2a. The Th17 cell population frequency was decreased and the Treg cell frequency was increased in the spleens of the DUSP5-treated group. The reciprocal regulation of Th17 and Treg cells in vivo was associated with attenuated activity of pSTAT-3 and pERK, and with increased activity of pSTAT-5. DUSP5 overexpression suppressed joint damage through down-regulation of pro-osteoclastogenic molecules.Conclusion. The antiarthritic properties of DUSP-5 are associated with its reciprocal regulation of Th17 and Treg cells and its inhibition of ERK activity.