TY - JOUR
T1 - Modulating CCR2 and CCL2 at the blood-brain barrier
T2 - Relevance for multiple sclerosis pathogenesis
AU - Mahad, Don
AU - Callahan, Melissa K.
AU - Williams, Katherine A.
AU - Ubogu, Eroboghene E.
AU - Kivisäkk, Pia
AU - Tucky, Barbara
AU - Kidd, Grahame
AU - Kingsbury, Gillian A.
AU - Chang, Ansi
AU - Fox, Robert J.
AU - Mack, Matthias
AU - Sniderman, M. Bradley
AU - Ravid, Rivka
AU - Staugaitis, Susan M.
AU - Stins, Monique F.
AU - Ransohoff, Richard M.
N1 - Funding Information:
This research was supported in part by the National Institutes of Health (NS38667 to RMR), postdoctoral fellowship FG1482 (to MKC) from the National Multiple Sclerosis Society and the Nancy Davis Center Without Walls. We acknowledge the MS Women’s Committee for providing support for imaging software and a computer station for image analysis. We acknowledge Cathy Shemo and Anne Cotleur for help with flow cytometry and phlebotomy, Jerome Wujek and Bruce Trapp for iba-1 monoclonal antibody and helpful comments about the data, Judith Drazba and the LRI Confocal Core for excellent technical assistance, and members of the Ransohoff lab for advice and suggestions.
PY - 2006/1
Y1 - 2006/1
N2 - 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.
AB - 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.
KW - CCL2/MCP-1
KW - CCR2
KW - Chemokine receptors
KW - Chemokines
KW - Multiple sclerosis
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U2 - 10.1093/brain/awh655
DO - 10.1093/brain/awh655
M3 - Article
C2 - 16230319
AN - SCOPUS:30344481086
VL - 129
SP - 212
EP - 223
JO - Brain
JF - Brain
SN - 0006-8950
IS - 1
ER -