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Activated leukocyte cell adhesion molecule promotes leukocyte trafficking into the central nervous system

Abstract

Adhesion molecules of the immunoglobulin superfamily are crucial effectors of leukocyte trafficking into the central nervous system. Using a lipid raft-based proteomic approach, we identified ALCAM as an adhesion molecule involved in leukocyte migration across the blood-brain barrier (BBB). ALCAM expressed on BBB endothelium localized together with CD6 on leukocytes and with BBB endothelium transmigratory cups. ALCAM expression on BBB cells was upregulated in active multiple sclerosis and experimental autoimmune encephalomyelitis lesions. Moreover, ALCAM blockade restricted the transmigration of CD4+ lymphocytes and monocytes across BBB endothelium in vitro and in vivo and reduced the severity and delayed the time of onset of experimental autoimmune encephalomyelitis. Our findings indicate an important function for ALCAM in the recruitment of leukocytes into the brain and identify ALCAM as a potential target for the therapeutic dampening of neuroinflammation.

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Figure 1: ALCAM is expressed by resting human BBB endothelial cells and partially localizes to lipid rafts.
Figure 2: Proinflammatory cytokines upregulate ALCAM on BBB endothelial cells and promote the translocation of ALCAM to lipid rafts.
Figure 3: ALCAM is upregulated on CNS vessels in active multiple sclerosis lesions.
Figure 4: ALCAM expression in multiple sclerosis lesions.
Figure 5: Fewer inflammatory lesions and less demyelination and leukocyte transmigration in EAE mice treated with ALCAM-blocking antibody.
Figure 6: ALCAM contributes to human leukocyte migration in an in vitro model of the BBB.

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Acknowledgements

We thank M. Bernard and J. Laganière for technical assistance in the laboratory; C. Gaspar for critical reading of the manuscript; and J.P. Antel for human material and intellectual input. Supported by the Canadian Institutes of Health Research (Neuroscience Mental Health and Addiction; MOP-81088; Neuroinflammation training program, R.C., J.L.B., A.D.-D. and S.K.; and Senior Research Fellowship Phase 2, N.A.), the Multiple Sclerosis Society of Canada (A.P., R.C., J.L.B., A.D.-D., K.W., H.K. and I.I.), the Canadian Foundation for Innovation, the US National Multiple Sclerosis Society (B.B.), the Swiss National Science Foundation (B.B.), Fonds de la Recherche en Santé du Québec (A.P.), and the Center for Neuroscience in Zurich (K.K.).

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Contributions

R.C. did all experiments unless stated otherwise; A.P. and K.W. established BBB endothelial cell primary cultures and lipid raft purification; A.D.-D., I.I., S.K., N.A. and H.K. did some immunostaining and flow cytometry and discussed data; J.L.B. and S.D. assisted with EAE experiments; A.S.H. and D.S. did lipid raft proteomic analysis; R.M. and A.B. provided the human CNS material from the operating room; B.B. and K.K. did in vivo restimulation assays; R.C. and A.P. designed the experiments and prepared the manuscript; and A.P. secured the funding.

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Correspondence to Alexandre Prat.

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Cayrol, R., Wosik, K., Berard, J. et al. Activated leukocyte cell adhesion molecule promotes leukocyte trafficking into the central nervous system. Nat Immunol 9, 137–145 (2008). https://doi.org/10.1038/ni1551

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