Roles of the DOCK-D family proteins in a mouse model of neuroinflammation
Roles of the DOCK-D family proteins in a mouse model of neuroinflammation
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DOI：
10.1074/jbc.ra119.010438
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发表时间：
2020-05-08
影响因子：
4.8
通讯作者：
Harada, Takayuki
中科院分区：
文献类型：
--
作者：
Namekata, Kazuhiko;Guo, Xiaoli;Harada, Takayuki
DOCK-D（胞质分裂 D 贡献者）家族蛋白是调节 Rho GTP 酶活性的非典型鸟嘌呤核苷酸交换因子。该家族由 Zizimin1 (DOCK9)、Zizimin2 (DOCK11) 和 Zizimin3 (DOCK10) 组成。 DOCK-D 家族蛋白的功能目前尚未得到充分探索，并且 DOCK-D 家族在神经炎症中的作用尚不清楚。在本研究中，我们生成了三个删除了 DOCK9 (DOCK9(?/?))、DOCK10 (DOCK10(?/?)) 或 DOCK11 (DOCK11(?/?)) 的小鼠品系，并检查了这些基因删除在 MOG(35?55) 肽诱导的实验性自身免疫性脑脊髓炎（一种神经炎症性疾病多发性硬化症的动物模型）中的表型效应。我们发现所有基因敲除系都是健康且有活力的。在正常条件下观察到的唯一表型是 DOCK10(?/?) 小鼠脾细胞中 B 细胞的比例略小于其他小鼠系。我们还发现 DOCK10(?/?) 和 DOCK11(?/?) 小鼠巨噬细胞的迁移能力受损，并且实验性自身免疫性脑脊髓炎的严重程度仅在 DOCK10(?/?) 小鼠中得到改善。 DOCK9(?/?) 小鼠没有观察到明显的表型。进一步的研究表明，脂多糖刺激上调小胶质细胞中 DOCK10 的表达，并且 DOCK10(?/?) 小鼠中小胶质细胞的迁移减少。与 WT 星形胶质细胞相比，DOCK10(?/?) 星形胶质细胞中由 Toll 样受体 4 或 9 信号传导激活诱导的 C?C 基序趋化因子配体 2 (CCL2) 表达上调减少。综上所述，我们的研究结果表明 DOCK10 在先天免疫和神经炎症中发挥作用，并可能代表治疗多发性硬化症的潜在治疗靶点。
The DOCK-D (dedicator of cytokinesis D) family proteins are atypical guanine nucleotide exchange factors that regulate Rho GTPase activity. The family consists of Zizimin1 (DOCK9), Zizimin2 (DOCK11), and Zizimin3 (DOCK10). Functions of the DOCK-D family proteins are presently not well-explored, and the role of the DOCK-D family in neuroinflammation is unknown. In this study, we generated three mouse lines in which DOCK9 (DOCK9(?/?)), DOCK10 (DOCK10(?/?)), or DOCK11 (DOCK11(?/?)) had been deleted and examined the phenotypic effects of these gene deletions in MOG(35?55) peptide-induced experimental autoimmune encephalomyelitis, an animal model of the neuroinflammatory disorder multiple sclerosis. We found that all the gene knockout lines were healthy and viable. The only phenotype observed under normal conditions was a slightly smaller proportion of B cells in splenocytes in DOCK10(?/?) mice than in the other mouse lines. We also found that the migration ability of macrophages is impaired in DOCK10(?/?) and DOCK11(?/?) mice and that the severity of experimental autoimmune encephalomyelitis was ameliorated only in DOCK10(?/?) mice. No apparent phenotype was observed for DOCK9(?/?) mice. Further investigations indicated that lipopolysaccharide stimulation up-regulates DOCK10 expression in microglia and that microglial migration is decreased in DOCK10(?/?) mice. Up-regulation of C?C motif chemokine ligand 2 (CCL2) expression induced by activation of Toll-like receptor 4 or 9 signaling was reduced in DOCK10(?/?) astrocytes compared with WT astrocytes. Taken together, our findings suggest that DOCK10 plays a role in innate immunity and neuroinflammation and might represent a potential therapeutic target for managing multiple sclerosis.