IFN-Inducible Protein 10/CXC Chemokine Ligand 10-Independent Induction of Experimental Autoimmune Encephalomyelitis

Monocyte recruitment to the central nervous system (CNS) is a necessary step in the development of pathologic inflammatory lesions in experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis. Monocyte chemoattractant protein (MCP)-1, a potent agonist for directed monocyte migration, has been implicated in the pathogenesis of EAE. Here we report that deficiency in CC chemokine receptor (CCR)2, the receptor for MCP-1, confers resistance to EAE induced with a peptide derived from myelin oligodendrocyte glycoprotein peptide 35–55 (MOGp35–55). CCR2−/− mice immunized with MOGp35–55 failed to develop mononuclear cell inflammatory infiltrates in the CNS and failed to increase CNS levels of the chemokines RANTES (regulated on activation, normal T cell expressed and secreted), MCP-1, and interferon (IFN)-inducible protein 10 (IP-10) as well the chemokine receptors CCR1, CCR2, and CCR5. Additionally, T cells from CCR2−/− immunized mice showed decreased antigen-induced proliferation and production of IFN-γ compared with wild-type immunized controls, suggesting that CCR2 enhances the T helper cell type 1 immune response in EAE. These data indicate that CCR2 plays a necessary and nonredundant role in the pathogenesis of EAE.

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CXCL10 (IFN-γ-Inducible Protein-10) Control of Encephalitogenic CD4+T Cell Accumulation in the Central Nervous System During Experimental Autoimmune Encephalomyelitis

The Journal of Immunology ◽

10.4049/jimmunol.166.12.7617 ◽

2001 ◽

Vol 166 (12) ◽

pp. 7617-7624 ◽

Cited By ~ 190

Author(s):

Brian T. Fife ◽

Kevin J. Kennedy ◽

Mary C. Paniagua ◽

Nicholas W. Lukacs ◽

Steven L. Kunkel ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Experimental Autoimmune Encephalomyelitis ◽

Cd4 T Cell ◽

Autoimmune Encephalomyelitis ◽

Cell Accumulation ◽

The Central Nervous System ◽

Ifn Γ ◽

Inducible Protein ◽

Experimental Autoimmune

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CXC Chemokine Receptors Expression during Chronic Relapsing Experimental Autoimmune Encephalomyelitis

Annals of the New York Academy of Sciences ◽

10.1111/j.1749-6632.2000.tb05377.x ◽

2006 ◽

Vol 917 (1) ◽

pp. 135-144 ◽

Cited By ~ 23

Author(s):

ANDRZEJ R. GLABINSKI ◽

SAGE O'BRYANT ◽

KRZYSZTOF SELMAJ ◽

RICHARD M. RANSOHOFF

Keyword(s):

Experimental Autoimmune Encephalomyelitis ◽

Chemokine Receptors ◽

Autoimmune Encephalomyelitis ◽

Cxc Chemokine ◽

Experimental Autoimmune

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

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.010438 ◽

2020 ◽

Vol 295 (19) ◽

pp. 6710-6720

Author(s):

Kazuhiko Namekata ◽

Xiaoli Guo ◽

Atsuko Kimura ◽

Yuriko Azuchi ◽

Yuta Kitamura ◽

...

Keyword(s):

Multiple Sclerosis ◽

Experimental Autoimmune Encephalomyelitis ◽

Rho Gtpase ◽

Gene Knockout ◽

Nucleotide Exchange ◽

Autoimmune Encephalomyelitis ◽

Migration Ability ◽

Chemokine Ligand ◽

Mouse Lines ◽

Experimental Autoimmune

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.

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