Roles of the DOCK-D family proteins in a mouse model of neuroinflammation.

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 (), (), or () had been deleted and examined the phenotypic effects of these gene deletions in MOG 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 mice than in the other mouse lines. We also found that the migration ability of macrophages is impaired in and mice and that the severity of experimental autoimmune encephalomyelitis was ameliorated only in mice. No apparent phenotype was observed for mice. Further investigations indicated that lipopolysaccharide stimulation up-regulates expression in microglia and that microglial migration is decreased in 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 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.