CXCL12-induced monocyte-endothelial interactions promote lymphocyte transmigration across an in vitro blood-brain barrier.
The accumulation of inflammatory cells in the brain parenchyma is a critical step in the pathogenesis of neuroinflammatory diseases such as multiple sclerosis (MS). Chemokines and adhesion molecules orchestrate leukocyte transmigration across the blood-brain barrier (BBB), but the dynamics of chemokine receptor expression during leukocyte transmigration are unclear. We describe an in vitro BBB model system using human brain microvascular endothelial cells that incorporates shear forces mimicking blood flow to elucidate how chemokine receptor expression is modulated during leukocyte transmigration. In the presence of the chemokine CXCL12, we examined modulation of its receptor CXCR4 on human T cells, B cells, and monocytes transmigrating across the BBB under flow conditions. CXCL12 stimulated transmigration of CD4(+) and CD8(+) T cells, CD19(+) B cells, and CD14(+) monocytes. Transmigration was blocked by CXCR4-neutralizing antibodies. Unexpectedly, CXCL12 selectively down-regulated CXCR4 on transmigrating monocytes, but not T cells. Monocytes underwent preferential CXCL12-mediated adhesion to the BBB in vitro compared with lymphocytes. These findings provide new insights into leukocyte-endothelial interactions at the BBB under conditions mimicking blood flow and suggest that in vitro BBB models may be useful for identifying chemokine receptors that could be modulated therapeutically to reduce neuroinflammation in diseases such as MS.
Neuroinflammation Research Center, Department of Neuroscience, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Shumei
S
Man
Barbara
B
Tucky
Anne
A
Cotleur
Judith
J
Drazba
Yukio
Y
Takeshita
Richard M
RM
Ransohoff
D000328:Adult; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D018941:Antigens, CD19 / Q000378:metabolism; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D001402:B-Lymphocytes / Q000276:immunology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism*; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D018836:Inflammation Mediators / Q000378:metabolism*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology*; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D010477:Perfusion; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D012039:Regional Blood Flow; D015398:Signal Transduction / Q000187:drug effects; D013539:Simian virus 40 / Q000235:genetics / Q000276:immunology; D013314:Stress, Mechanical; D013997:Time Factors; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects; D014162:Transfection; D055815:Young Adult
D057134:Antibodies, Neutralizing; D018941:Antigens, CD19; D000952:Antigens, Polyomavirus Transforming; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D018836:Inflammation Mediators; D018950:Lipopolysaccharide Receptors; D019718:Receptors, CXCR4