title: Induction of inhibitory central nervous system-derived and stimulatory blood-derived dendritic cells suggests a dual role for granulocyte-macrophage colony-stimulating factor in central nervous system inflammation.
abstract: The mononuclear phagocyte system, particularly dendritic cells, plays several pivotal roles in the development of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Here, we demonstrate that functionally distinct dendritic cell subpopulations are present in the central nervous system during experimental autoimmune encephalomyelitis. At peak experimental autoimmune encephalomyelitis, the majority of dendritic cells consisted of a CD11b(+)F4/80(+) inflammatory dendritic cell subtype. Both granulocyte-macrophage colony-stimulating factor and chemokine (C-C motif) ligand 2 were previously suggested to recruit 'inflammatory' monocyte-derived dendritic cells to the central nervous system during experimental autoimmune encephalomyelitis. We show that intra-cerebral production of granulocyte-macrophage colony-stimulating factor leading to chemokine (C-C motif) ligand 2 induction and attraction of chemokine (C-C motif) receptor 2-positive precursors suffices to recruit dendritic cell populations identical to those observed in experimental autoimmune encephalomyelitis into the central nervous system of healthy mice. This does not occur with fms-like tyrosine kinase-3-ligand treatment. Both during experimental autoimmune encephalomyelitis and upon intra-cerebral granulocyte-macrophage colony-stimulating factor production, all myeloid dendritic cells, lymphoid dendritic cells and periphery-derived inflammatory dendritic cells stimulated T cell proliferation, whereas inflammatory dendritic cells that differentiated from central nervous system precursors inhibited T cell activation and pro-inflammatory cytokine production. Despite the capacity of granulocyte-macrophage colony-stimulating factor to induce central nervous system-derived inhibitory inflammatory dendritic cells, the administration of granulocyte-macrophage colony-stimulating factor into mice with experimental autoimmune encephalomyelitis resulted in exacerbated disease. Granulocyte-macrophage colony-stimulating factor thus has a dual role in the central nervous system: it directs both central nervous system-derived dendritic cells towards an inhibitory phenotype and recruits peripheral dendritic cells exhibiting pro-inflammatory functions.
authors.affiliation: Clinical Immunology, University Hospital of Zurich, Switzerland.
authors.forename: Lysann
authors.initials: L
authors.lastname: Hesske
authors.forename: Christine
authors.initials: C
authors.lastname: Vincenzetti
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwalder
authors.forename: Marco
authors.initials: M
authors.lastname: Prinz
authors.forename: Walter
authors.initials: W
authors.lastname: Reith
authors.forename: Adriano
authors.initials: A
authors.lastname: Fontana
authors.forename: Tobias
authors.initials: T
authors.lastname: Suter
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D001921:Brain / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D039481:CD11b Antigen / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism*; D013116:Spinal Cord / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000502:physiology; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism
chemical_list: D000943:Antigens, Differentiation; D039481:CD11b Antigen; D018925:Chemokines; D008565:Membrane Proteins; C084881:flt3 ligand protein; C036763:monocyte-macrophage differentiation antigen; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D051941:fms-Like Tyrosine Kinase 3