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 language | English (US) |
|---|---|
| Pages (from-to) | 212-223 |
| Number of pages | 12 |
| Journal | Brain |
| Volume | 129 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 2006 |
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Keywords
- CCL2/MCP-1
- CCR2
- Chemokine receptors
- Chemokines
- Multiple sclerosis
ASJC Scopus subject areas
- Neuroscience(all)
Cite this
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 journal › Article
}
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
AU - Ransohoff, Richard M.
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
UR - http://www.scopus.com/inward/record.url?scp=30344481086&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=30344481086&partnerID=8YFLogxK
U2 - 10.1093/brain/awh655
DO - 10.1093/brain/awh655
M3 - Article
VL - 129
SP - 212
EP - 223
JO - Brain
JF - Brain
SN - 0006-8950
IS - 1
ER -