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See Latest ArticlesAlpha 4 Integrin/FN-CS1 mediated leukocyte adhesion to brain microvascular endothelial cells under flow conditions
Journal of Neuroimmunology, 05/26/09
Man S et al. - These results established a novel in vitro dynamic BBB model. The authors also demonstrated the dependence of leukocyte-endothelial interactions in this model on alpha 4 integrins and FN-CS1.
Shumei Man, 06/16/09
| Leukocyte infiltration plays a key role in neuroinflammatory diseases. To study the multi-steps leukocyte extravasation process, it is necessary to develop an in vitro blood-brain barrier (ivBBB) model using brain derived endothelial cells under physiological flow conditions. Hemodynamic shear, a fundamental physiological feature, is crucial for apical chemokine deposits, integrin engagement, firm adhesion, locomotion, and transendothelial migration. This paper reports a dynamic ivBBB model to study leukocyte–brain endothelial interactions under flow conditions. To mimic inflammatory conditions, THBMEC were activated with proinflammatory cytokines TNF ? and IFN ? (aTHBMEC). Cytokines up-regulated certain chemokines and adhesion molecules in THBMEC. The results showed that brain derived endothelial cells (termed THBMEC) maintained intact morphology and tight junction structures under physiological flow conditions after cytokine treatment. Meanwhile, leukocyte adhesion to THBMEC was enhanced. Although the relationship between chemokine up-regulation and enhanced leukocyte adhesion is under study, blocking leukocyte Go/i receptor abrogated adhesion. Using this inflammatory ivBBB model, we visualized the effect of natalizumab, an anti-?4 integrin antibody, in MS treatment. The result shows that natalizumab infusion to MS patients inhibited adhesion of leukocytes analyzed directly ex-vivo from natalizumab treated patients to aTHBMEC, compared to those from MS patients treated with IFN?-1a. There has been a debate about the ligand of alpha4 integrin on brain endohthelial cells. Using the ivBBB model under flow condition, we found that alpha 4 integrin mediated leukocyte adhesion to brain endothelial cells via FN-CS1, not VCAM-1. The ivBBB model presented in this paper let us visualize the sequential process of leukocyte-brain endothelial interaction under flow conditions. It extended our understanding of alph4 integrin/FN-CS1 mediated leukocyte brain infiltration and anti-alpha 4 integrin antibody treatment for MS. It is a potential tool to evaluate drug effect in MS patients in terms of modifying leukocyte adhesion to brain endothelial cells. It is also invaluable for exploring new drugs to manage neuroinflammatory diseases. |
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