CXCR7 influences leukocyte entry into the CNS parenchyma by controlling abluminal CXCL12 abundance during autoimmunity
Open accessAbstract
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.
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In the MOG35-55 EAE model, CXCR7 expression on the abluminal side of endothelial cells binds CXCL12, limiting the ability of this chemokine to trap leukocytes in the perivascular space.
“Using the myelin oligodendrocyte glycoprotein (MOG35-55) immunization model of EAE, it was shown that CXCR7 expression on the abluminal side of endothelial cells binds CXCL12, limiting the ability of this chemokine to trap leukocytes in the perivascular space, as it does during steady state (Fig. 4) (115).”
From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [115]
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References 50 · Cited by 231
- Authors
- 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.
- Affiliations
- Department of Internal Medicine 1 , 2 , 3 , and 4
- Washington University in St. Louis (US)
- Northwestern University (US)
- ChemoCentryx (United States) (US)
- University of Michigan (US)
- New York University (US)
- Corresponding author
- Klein, Robyn S.
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2011-02-07
- Volume
- 208
- Issue
- 2
- Pages
- 327-339
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC3039853
- OpenAlex
- W2161766823
- Cited by
- 231
- References
- 50
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 12 · 2023: 10 · 2022: 14 · 2021: 15 · 2020: 21 · 2019: 14 · 2018: 10 · 2017: 15 · 2016: 11 · 2015: 18 · 2014: 24 · 2013: 16 · 2012: 29
- FWCI
- 12.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-sa)
- Funders
- Multiple Sclerosis Society
- National Institutes of Health
- National Cancer Institute (R01CA136829, R01CA136553, P50CA093990)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK105562)
- National Institute of Neurological Disorders and Stroke (NS059560, P01NS059560)
- Topics
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Keywords
- CXCR7, CXCL12, blood-brain barrier, experimental autoimmune encephalomyelitis, multiple sclerosis, brain endothelial cells, VCAM-1, IL-17, IL-1β, interferon-gamma, autoimmunity
- MeSH terms
- Analysis of Variance, Animals, Blood-Brain Barrier, Cell Movement, Chemotaxis, Leukocyte, Flow Cytometry, Immunohistochemistry, Mice, Inbred C57BL, Spinal Cord, T-Lymphocytes, Autoimmunity, Polymerase Chain Reaction, Cell Proliferation, Mice, Chemokine CXCL12, Receptors, CXCR, Gene Knock-In Techniques
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