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 MOG35-55 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.

中文翻译：

---

DOCK-D家族蛋白在小鼠神经炎症模型中的作用。

DOCK-D（细胞分裂D的专用剂）家族蛋白是调节Rho GTPase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。目前还没有很好地研究DOCK-D家族蛋白的功能，并且尚不清楚DOCK-D家族在神经炎症中的作用。在这项研究中，我们生成了三种小鼠系，其中删除了DOCK9（DOCK9-/-），DOCK10（DOCK10-/-）或DOCK11（DOCK11-/-），并检查了MOG35-中这些基因缺失的表型效应。 55肽诱导的实验性自身免疫性脑脊髓炎，这是一种神经炎性多发性硬化症的动物模型。我们发现所有基因敲除品系都是健康且可行的。在正常条件下观察到的唯一表型是DOCK10-/-小鼠脾细胞中B细胞的比例略低于其他小鼠系。我们还发现，巨噬细胞的迁移能力在DOCK10-/-和DOCK11-/-小鼠中受损，并且实验性自身免疫性脑脊髓炎的严重性仅在DOCK10-/-小鼠中得到改善。对于DOCK9-/-小鼠没有观察到明显的表型。进一步的研究表明，脂多糖刺激上调了小胶质细胞中DOCK10的表达，而DOCK10-/-小鼠中的小胶质细胞迁移减少了。与WT星形胶质细胞相比，DOCK10-/-星形胶质细胞减少了由Toll样受体4或9信号的激活诱导的CC基序趋化因子配体2（CCL2）表达的上调。在一起