title: CCR2-dependent dendritic cell accumulation in the central nervous system during early effector experimental autoimmune encephalomyelitis is essential for effector T cell restimulation in situ and disease progression.
abstract: Dendritic cells (DCs)--although absent from the healthy CNS parenchyma--rapidly accumulate within brain and spinal cord tissue during neuroinflammation associated with experimental autoimmune encephalomyelitis (EAE; a mouse model of multiple sclerosis). Yet, although DCs have been appreciated for their role in initiating adaptive immune responses in peripheral lymphoid organ tissues, how DCs infiltrate the CNS and contribute to ongoing neuroinflammation in situ is poorly understood. In this study, we report the following: 1) CD11c(+) bone marrow-derived DCs and CNS-infiltrating DCs express chemokine receptor CCR2; 2) compared with CCR2(+/+) cells, adoptively transferred CCR2(-/-) bone marrow-derived DCs or DC precursors do not accumulate in the CNS during EAE, despite abundance in blood; 3) CCR2(-/-) DCs show less accumulation in the inflamed CNS in mixed bone marrow chimeras, when compared with CCR2(+/+) DCs; and 4) ablation of CCR2(+/+) DCs during EAE clinical onset delays progression and attenuates cytokine production by infiltrating T cells. Whereas the role of CCR2 in monocyte migration into the CNS has been implicated previously, the role of CCR2 in DC infiltration into the CNS has never been directly addressed. Our data suggest that CCR2-dependent DC recruitment to the CNS during ongoing neuroinflammation plays a crucial role in effector T cell cytokine production and disease progression, and signify that CNS-DCs and circulating DC precursors might be key therapeutic targets for suppressing ongoing neuroinflammation in CNS autoimmune diseases.
authors.affiliation: Department of Pathology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792; Department of Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792; Graduate Training Program of Cellular and Molecular Pathology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792; and.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Clarkson
authors.affiliation: Department of Pathology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792; Department of Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792;
authors.forename: Alec
authors.initials: A
authors.lastname: Walker
authors.affiliation: Department of Pathology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792; Department of Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792;
authors.forename: Melissa G
authors.initials: MG
authors.lastname: Harris
authors.affiliation: Graduate Training Program of Neuroscience, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792.
authors.forename: Aditya
authors.initials: A
authors.lastname: Rayasam
authors.affiliation: Department of Pathology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792; Department of Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792;
authors.forename: Matyas
authors.initials: M
authors.lastname: Sandor
authors.affiliation: Department of Pathology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792; Department of Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792; zfabry@wisc.edu.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Fabry
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000473:pathology; D016026:Bone Marrow Transplantation; D001921:Brain / Q000276:immunology* / Q000473:pathology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000473:pathology; D054390:Receptors, CCR2 / Q000235:genetics / Q000276:immunology*; D013116:Spinal Cord / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018183:Transplantation Chimera / Q000276:immunology
chemical_list: C515335:Ccr2 protein, mouse; D016207:Cytokines; D054390:Receptors, CCR2