CXCR7 influences leukocyte entry into the CNS parenchyma by controlling abluminal CXCL12 abundance during autoimmunity

Lillian Cruz-Orengo, David W. Holman, Denise Dorsey, Liang Zhou, Penglie Zhang, Melissa Wright, Erin E. McCandless, Jigisha R. Patel, Gary D. Luker, Dan R. Littman, John H. Russell, Robyn S. Klein

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130 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)327-339
Number of pages13
JournalJournal of Experimental Medicine
Volume208
Issue number2
DOIs
StatePublished - Feb 14 2011
Externally publishedYes

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Cruz-Orengo, L., Holman, D. W., Dorsey, D., Zhou, L., Zhang, P., Wright, M., McCandless, E. E., Patel, J. R., Luker, G. D., Littman, D. R., Russell, J. H., & Klein, R. S. (2011). CXCR7 influences leukocyte entry into the CNS parenchyma by controlling abluminal CXCL12 abundance during autoimmunity. Journal of Experimental Medicine, 208(2), 327-339. https://doi.org/10.1084/jem.20102010