The role of Cas-L/NEDD9 as a regulator of collagen-induced arthritis in a murine model
The role of Cas-L/NEDD9 as a regulator of collagen-induced arthritis in a murine model
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DOI：
10.1016/j.bbrc.2015.03.156
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发表时间：
2015-05-15
影响因子：
3.1
通讯作者：
Morimoto，Chikao
中科院分区：
文献类型：
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作者：
Katayose，Tomoki;Iwata，Satoshi;Morimoto，Chikao
Cas-L/NEDD9是β1整合素介导的信号通路下游的细胞质对接蛋白，对细胞迁移和β1整合素介导的T细胞共刺激至关重要。我们之前发现，更多的casl阳性白细胞迁移到HTLV-I转基因小鼠的炎症关节中，这些小鼠自发发展为多发性关节炎，这表明casl在类风湿关节炎（RA）的病理生理中起作用。我们目前的研究通过分析aNedd9 - / -小鼠胶原诱导关节炎（CIA）模型的病理生理变化，扩展了Cas-L/NEDD9在RA发展中的作用。与toNedd9+/+小鼠相比，Nedd9−/−小鼠的关节炎严重程度有所降低。此外，通过CIA模型进行骨髓移植实验，Nedd9 - / -→Nedd9+/+移植比Nedd9+/+→Nedd9 - / -移植的关节炎发病率和严重程度评分降低。血清中各种细胞因子水平分析显示，与nedd9 +/+小鼠相比，nedd9−/−小鼠的IL-1β、IL-6、IL-17、TNF-α、IFN-γ和抗胶原抗体水平降低，IL-4和IL-10水平升高。此外，从nedd9−/−小鼠脾脏或受累淋巴结分离的淋巴细胞胶原介导的细胞反应降低。我们的研究结果强烈提示Cas-L/NEDD9在CIA的病理生理中起着关键作用，并且Cas-L/NEDD9可能是治疗RA的潜在分子靶点。
Cas-L/NEDD9 is a cytoplasmic docking protein downstream of β1 integrin-mediated signaling pathway and is essential for cellular migration and β1 integrin-mediated costimulation of T cells. We previously found that increased number of Cas-L positive leukocytes migrated into the inflamed joints of HTLV-I tax transgenic mice which spontaneously develop polyarthritis, suggesting a role of Cas-L in rheumatoid arthritis (RA) pathophysiology. Our current study expanded these findings on the role of Cas-L/NEDD9 in the development of RA by analyzing the pathophysiological changes in aNedd9−/−mouse collagen-induced arthritis (CIA) model.Nedd9−/−mice exhibited a decrease in arthritis severity as compared toNedd9+/+mice. In addition, as being conducted bone marrow transplantation experiments with a CIA model,Nedd9−/−→Nedd9+/+transplant showed a decrease in the incidence and severity score of arthritis, compared to those ofNedd9+/+→Nedd9−/−transplant. For analysis of serum levels of various cytokines, IL-1β, IL-6, IL-17, TNF-α, IFN-γ and anti-collagen antibody were decreased, while IL-4 and IL-10 levels were increased, inNedd9−/−mice as compared to those inNedd9+/+mice. Furthermore, collagen-mediated cellular responses of lymphocytes isolated from spleen or affected lymph nodes ofNedd9−/−mice were reduced. Our results strongly suggest that Cas-L/NEDD9 plays a pivotal role in the pathophysiology of CIA, and that Cas-L/NEDD9 may be a potential molecular target for the treatment of RA.