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Chemokines regulation of immune cell recruitment across the blood-brain barrier in inflammation

University of British Columbia

A key element of the inflammatory response in the central nervous system (CNS) is the recruitment of leukocytes across the blood-brain barrier (BBB) that normally restricts their passage from blood to brain. Endothelial cell (EC) adhesion molecules and chemokines have emerged as important mediators of leukocyte recruitment to the CNS. The objective of this study was to characterize the kinetics of expression and release of the chemokine CXCL12 by human brain microvessel EC (HBMEC) and to investigate the effects of CXCL12 and the beta-chemokines CCL2 and CCL3 on the adhesion and migration of T cell subsets and monocytes across an in vitro model of the BBB. Cytokines and LPS downregulated the constitutive CXCL12 and CXCR4 expression and CXCL12 ligation induced internalization of CXCR4. Monocyte and T cell adhesion and migration in response to these chemokines were studied in a double chamber chemotaxis system in the presence of chemokine concentration gradients. The minimal adhesion and migration of CD4+ and CD8+ T lymphocytes were significantly increased after cytokine treatment of HBMEC. CXCL12 gradients further enhanced adhesion of both T cell subsets to activated HBMEC and migration across resting monolayers. Concentration gradients of CCL2 increased adhesion of activated CD4+ T cells to cytokine treated HBMEC, whereas CCL3 increased adhesion of memory CD4+ T cells to resting HBMEC. Migration of resting, activated, naïve and memory CD4+ T cells across resting and cytokine treated HBMEC was augmented in the presence of CCL2 or CCL3 in the subendothelial compartment. The number of migrated resting and naïve CD4+ T cells across resting HBMEC was slightly decreased by CCL3. Neither CCL2 nor CCL3 had any significant effect on monocyte adhesion, however, both chemokines significantly increased monocyte migration across resting HBMEC. Monocyte adhesion and migration across cytokine treated HBMEC were dependent upon integrins and EC adhesion molecules, since blocking ICAM-1, beta2- or alpha4-integrins significantly reduced transendothelial migration. These studies emphasize the importance of cerebral EC activation and the role of CXCL12, CCL2 and CCL3 in regulating the directional migration of T cell subsets and monocytes across the BBB, thus contributing to the specificity of immune responses in neuroinflammation.

Thesis/Dissertation

application/pdf

2009-10-29

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/14409

Pathology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/