title: CXCR7 influences leukocyte entry into the CNS parenchyma by controlling abluminal CXCL12 abundance during autoimmunity.
abstract: Loss of CXCL12, a leukocyte localizing cue, from abluminal surfaces of the blood-brain barrier occurs in multiple sclerosis (MS) lesions. However, the mechanisms and consequences of reduced abluminal CXCL12 abundance remain unclear. Here, we show that activation of CXCR7, which scavenges CXCL12, is essential for leukocyte entry via endothelial barriers into the central nervous system (CNS) parenchyma during experimental autoimmune encephalomyelitis (EAE), a model for MS. CXCR7 expression on endothelial barriers increased during EAE at sites of inflammatory infiltration. Treatment with a CXCR7 antagonist ameliorated EAE, reduced leukocyte infiltration into the CNS parenchyma and parenchymal VCAM-1 expression, and increased abluminal levels of CXCL12. Interleukin 17 and interleukin 1β increased, whereas interferon-γ decreased, CXCR7 expression on and CXCL12 internalization in primary brain endothelial cells in vitro. These findings identify molecular requirements for the transvascular entry of leukocytes into the CNS and suggest that CXCR7 blockade may have therapeutic utility for the treatment of MS.
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Lillian
authors.initials: L
authors.lastname: Cruz-Orengo
authors.forename: David W
authors.initials: DW
authors.lastname: Holman
authors.forename: Denise
authors.initials: D
authors.lastname: Dorsey
authors.forename: Liang
authors.initials: L
authors.lastname: Zhou
authors.forename: Penglie
authors.initials: P
authors.lastname: Zhang
authors.forename: Melissa
authors.initials: M
authors.lastname: Wright
authors.forename: Erin E
authors.initials: EE
authors.lastname: McCandless
authors.forename: Jigisha R
authors.initials: JR
authors.lastname: Patel
authors.forename: Gary D
authors.initials: GD
authors.lastname: Luker
authors.forename: Dan R
authors.initials: DR
authors.lastname: Littman
authors.forename: John H
authors.initials: JH
authors.lastname: Russell
authors.forename: Robyn S
authors.initials: RS
authors.lastname: Klein
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D001812:Blood-Brain Barrier / Q000276:immunology* / Q000378:metabolism; D002465:Cell Movement / Q000276:immunology*; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D005434:Flow Cytometry; D055879:Gene Knock-In Techniques; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D054387:Receptors, CXCR / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D054377:Chemokine CXCL12; C501897:Cmkor1 protein, mouse; D054387:Receptors, CXCR