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

The dedicator of cytokinesis D (DOCK-D) family proteins are atypical guanine nucleotide exchange factors (GEFs) 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 (EAE), an animal model of the neuroinflammatory disorder multiple sclerosis (MS). 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 EAE 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 (TLR) 4 or TLR9 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 MS.