T lymphocytes impair P-glycoprotein function during neuroinflammation.
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.
Kooij
Gijs
G
Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
van Horssen
Jack
J
de Lange
Elizabeth C M
EC
Reijerkerk
Arie
A
van der Pol
Susanne M A
SM
van Het Hof
Bert
B
Drexhage
Joost
J
Vennegoor
Anke
A
Killestein
Joep
J
Scheffer
George
G
Oerlemans
Ruud
R
Scheper
Rik
R
van der Valk
Paul
P
Dijkstra
Christine D
CD
de Vries
Helga E
HE
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*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1