title: T lymphocytes impair P-glycoprotein function during neuroinflammation.
abstract: 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-kappaB) 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.
authors: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors: Gijs
authors: G
authors: Kooij
authors: Jack
authors: J
authors: van Horssen
authors: Elizabeth C M
authors: EC
authors: de Lange
authors: Arie
authors: A
authors: Reijerkerk
authors: Susanne M A
authors: SM
authors: van der Pol
authors: Bert
authors: B
authors: van Het Hof
authors: Joost
authors: J
authors: Drexhage
authors: Anke
authors: A
authors: Vennegoor
authors: Joep
authors: J
authors: Killestein
authors: George
authors: G
authors: Scheffer
authors: Ruud
authors: R
authors: Oerlemans
authors: Rik
authors: R
authors: Scheper
authors: Paul
authors: P
authors: van der Valk
authors: Christine D
authors: CD
authors: Dijkstra
authors: Helga E
authors: HE
authors: de Vries
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000502:physiology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001921:Brain / Q000473:pathology*; D001923:Brain Chemistry; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D015213:Neuroimmunomodulation; D051381:Rats; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000473:pathology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1