title: CC chemokine receptor 4 is required for experimental autoimmune encephalomyelitis by regulating GM-CSF and IL-23 production in dendritic cells.
abstract: Dendritic cells (DCs) are pivotal for the development of experimental autoimmune encephalomyelitis (EAE). However, the mechanisms by which they control disease remain to be determined. This study demonstrates that expression of CC chemokine receptor 4 (CCR4) by DCs is required for EAE induction. CCR4(-/-) mice presented enhanced resistance to EAE associated with a reduction in IL-23 and GM-CSF expression in the CNS. Restoring CCR4 on myeloid cells in bone marrow chimeras or intracerebral microinjection of CCR4-competent DCs, but not macrophages, restored EAE in CCR4(-/-) mice, indicating that CCR4(+) DCs are cellular mediators of EAE development. Mechanistically, CCR4(-/-) DCs were less efficient in GM-CSF and IL-23 production and also T(H)-17 maintenance. Intraspinal IL-23 reconstitution restored EAE in CCR4(-/-) mice, whereas intracerebral inoculation using IL-23(-/-) DCs or GM-CSF(-/-) DCs failed to induce disease. Thus, CCR4-dependent GM-CSF production in DCs required for IL-23 release in these cells is a major component in the development of EAE. Our study identified a unique role for CCR4 in regulating DC function in EAE, harboring therapeutic potential for the treatment of CNS autoimmunity by targeting CCR4 on this specific cell type.
authors.affiliation: Institute of Molecular Psychiatry, University of Bonn, 53127 Bonn, Germany.
authors.forename: Karola
authors.initials: K
authors.lastname: Poppensieker
authors.forename: David-Marian
authors.initials: DM
authors.lastname: Otte
authors.forename: Britta
authors.initials: B
authors.lastname: Schürmann
authors.forename: Andreas
authors.initials: A
authors.lastname: Limmer
authors.forename: Philipp
authors.initials: P
authors.lastname: Dresing
authors.forename: Eva
authors.initials: E
authors.lastname: Drews
authors.forename: Beatrix
authors.initials: B
authors.lastname: Schumak
authors.forename: Luisa
authors.initials: L
authors.lastname: Klotz
authors.forename: Jennifer
authors.initials: J
authors.lastname: Raasch
authors.forename: Alexander
authors.initials: A
authors.lastname: Mildner
authors.forename: Ari
authors.initials: A
authors.lastname: Waisman
authors.forename: Stefanie
authors.initials: S
authors.lastname: Scheu
authors.forename: Percy
authors.initials: P
authors.lastname: Knolle
authors.forename: Irmgard
authors.initials: I
authors.lastname: Förster
authors.forename: Marco
authors.initials: M
authors.lastname: Prinz
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Maier
authors.forename: Andreas
authors.initials: A
authors.lastname: Zimmer
authors.forename: Judith
authors.initials: J
authors.lastname: Alferink
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D003713:Dendritic Cells / Q000166:cytology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D007249:Inflammation; D053759:Interleukin-23 / Q000378:metabolism*; D008024:Ligands; D008264:Macrophages / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D054398:Receptors, CCR4 / Q000378:metabolism / Q000502:physiology*
chemical_list: C515355:Ccr4 protein, mouse; D053759:Interleukin-23; D008024:Ligands; D054398:Receptors, CCR4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor