Journal
JOURNAL OF AUTOIMMUNITY
Volume 34, Issue 4, Pages 416-425Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jaut.2009.10.006
Keywords
P-Glycoprotein; Blood-brain barrier; Multiple sclerosis; Experimental allergic encephalomyelitis; T cells; Nuclear factor kappa B
Categories
Funding
- Netherlands Organization of Scientific Research [016.046.314]
- Dutch foundation of MS Research, The Netherlands [MS 02-358, MS 05-567, MS 05-358c]
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The ATP-binding cassette (ABC) transporter P-glycoprotein (P-gp; ABCB1) is highly expressed at the blood brain barrier (BBB). P-gp actively secretes and keeps the central nervous system (CNS) safe from body-born metabolites, but also from drugs and food components, emphasising the importance of its optimal function to maintain brain homeostasis. Here we demonstrate that vascular P-gp expression and function are strongly decreased during neuroinflammation. In vivo, the expression and function of brain endothelial P-gp in experimental allergic encephalomyelitis (EAE), an animal model for multiple sclerosis (MS), were significantly impaired. Strikingly, vascular P-gp expression was decreased in both MS and EAE lesions and its disappearance coincided with the presence of perivascular infiltrates consisting of lymphocytes. Our data strongly suggest that activated CD4(+) T cells induce impaired function of brain endothelial P-gp. Notably, lymphocyte interaction through endothelial intracellular adhesion molecule 1 (ICAM-1) resulted in activation of a nuclear factor kappa B (NF-kappa B) signaling pathway, which resulted in endothelial P-gp malfunction. Our study provides first evidence that CD4(+) T cells are able to affect endogenous molecular protection mechanisms of brain endothelium. Loss of vascular P-gp function during neuroinflammation may disturb brain homeostasis and thereby aggravate disease progression via exposure of vulnerable CNS cells to detrimental compounds. (C) 2009 Elsevier Ltd. All rights reserved.
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