Modulating CCR2 and CCL2 at the blood-brain barrier

Relevance for multiple sclerosis pathogenesis

Don Mahad, Melissa K. Callahan, Katherine A. Williams, Eroboghene E. Ubogu, Pia Kivisäkk, Barbara Tucky, Grahame Kidd, Gillian A. Kingsbury, Ansi Chang, Robert J. Fox, Matthias Mack, M. Bradley Sniderman, Rivka Ravid, Susan M. Staugaitis, Monique Stins, Richard M. Ransohoff

Research output: Contribution to journalArticle

Abstract

Chemokines and chemokine receptors play a key role in the transmigration of leucocytes across the blood-brain barrier (BBB). CCR2 is the major receptor for CCL2, a potent monocyte and T cell chemoattractant. CCR2 and CCL2 have been consistently associated with a pathogenic role in experimental autoimmune encephalomyelitis, using knockout and transgenic mice, neutralizing antibodies, peptide antagonists and DNA vaccination. However, the significance of CCL2 and CCR2 in multiple sclerosis is enigmatic, because CCL2 levels are consistently decreased in the CSF of patients with this disease and other chronic neuroinflammatory conditions, despite abundant expression within lesional multiple sclerosis tissues. This study used an in vitro BBB model to test the hypothesis that CCL2 is removed from the extracellular fluid by CCR2-positive migrating cells as they cross the BBB, resulting in decreased CSF CCL2 levels. We showed that CCR2-positive T cells and monocytes migrated selectively across the in vitro BBB, and that CCL2 on the abluminal (tissue) side was consumed by migrating T cells and monocytes. Next, we used a new anti-CCR2 antibody to show that CCR2-positive mononuclear inflammatory cells could be readily detected in appropriate positive control tissues, but that CCR2+ cells were very infrequently found in multiple sclerosis lesions. We then showed that CCR2 receptor density on T cells and monocytes was specifically downregulated upon in vitro BBB transmigration in response to CCL2, but not irrelevant chemokines. These findings document a novel strategy for analysing chemokine receptor function in inflammatory CNS disease, and support the hypothesis that CCL2 is consumed by migrating inflammatory cells, which downregulate CCR2, as they cross the BBB.

Original languageEnglish (US)
Pages (from-to)212-223
Number of pages12
JournalBrain
Volume129
Issue number1
DOIs
StatePublished - Jan 2006

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Blood-Brain Barrier
Multiple Sclerosis
Monocytes
T-Lymphocytes
Chemokine Receptors
Chemokines
Down-Regulation
CCR2 Receptors
Autoimmune Experimental Encephalomyelitis
Central Nervous System Diseases
Chemotactic Factors
Extracellular Fluid
Neutralizing Antibodies
Knockout Mice
Transgenic Mice
Anti-Idiotypic Antibodies
Vaccination
Leukocytes
Chronic Disease
Peptides

Keywords

  • CCL2/MCP-1
  • CCR2
  • Chemokine receptors
  • Chemokines
  • Multiple sclerosis

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Mahad, D., Callahan, M. K., Williams, K. A., Ubogu, E. E., Kivisäkk, P., Tucky, B., ... Ransohoff, R. M. (2006). Modulating CCR2 and CCL2 at the blood-brain barrier: Relevance for multiple sclerosis pathogenesis. Brain, 129(1), 212-223. https://doi.org/10.1093/brain/awh655

Modulating CCR2 and CCL2 at the blood-brain barrier : Relevance for multiple sclerosis pathogenesis. / Mahad, Don; Callahan, Melissa K.; Williams, Katherine A.; Ubogu, Eroboghene E.; Kivisäkk, Pia; Tucky, Barbara; Kidd, Grahame; Kingsbury, Gillian A.; Chang, Ansi; Fox, Robert J.; Mack, Matthias; Sniderman, M. Bradley; Ravid, Rivka; Staugaitis, Susan M.; Stins, Monique; Ransohoff, Richard M.

In: Brain, Vol. 129, No. 1, 01.2006, p. 212-223.

Research output: Contribution to journalArticle

Mahad, D, Callahan, MK, Williams, KA, Ubogu, EE, Kivisäkk, P, Tucky, B, Kidd, G, Kingsbury, GA, Chang, A, Fox, RJ, Mack, M, Sniderman, MB, Ravid, R, Staugaitis, SM, Stins, M & Ransohoff, RM 2006, 'Modulating CCR2 and CCL2 at the blood-brain barrier: Relevance for multiple sclerosis pathogenesis', Brain, vol. 129, no. 1, pp. 212-223. https://doi.org/10.1093/brain/awh655
Mahad D, Callahan MK, Williams KA, Ubogu EE, Kivisäkk P, Tucky B et al. Modulating CCR2 and CCL2 at the blood-brain barrier: Relevance for multiple sclerosis pathogenesis. Brain. 2006 Jan;129(1):212-223. https://doi.org/10.1093/brain/awh655
Mahad, Don ; Callahan, Melissa K. ; Williams, Katherine A. ; Ubogu, Eroboghene E. ; Kivisäkk, Pia ; Tucky, Barbara ; Kidd, Grahame ; Kingsbury, Gillian A. ; Chang, Ansi ; Fox, Robert J. ; Mack, Matthias ; Sniderman, M. Bradley ; Ravid, Rivka ; Staugaitis, Susan M. ; Stins, Monique ; Ransohoff, Richard M. / Modulating CCR2 and CCL2 at the blood-brain barrier : Relevance for multiple sclerosis pathogenesis. In: Brain. 2006 ; Vol. 129, No. 1. pp. 212-223.
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