title: Adenosine triphosphate-binding cassette transporters mediate chemokine (C-C motif) ligand 2 secretion from reactive astrocytes: relevance to multiple sclerosis pathogenesis.
abstract: Adenosine triphosphate-binding cassette efflux transporters are highly expressed at the blood-brain barrier and actively hinder passage of harmful compounds, thereby maintaining brain homoeostasis. Since, adenosine triphosphate-binding cassette transporters drive cellular exclusion of potential neurotoxic compounds or inflammatory molecules, alterations in their expression and function at the blood-brain barrier may contribute to the pathogenesis of neuroinflammatory disorders, such as multiple sclerosis. Therefore, we investigated the expression pattern of different adenosine triphosphate-binding cassette efflux transporters, including P-glycoprotein, multidrug resistance-associated proteins-1 and -2 and breast cancer resistance protein in various well-characterized human multiple sclerosis lesions. Cerebrovascular expression of P-glycoprotein was decreased in both active and chronic inactive multiple sclerosis lesions. Interestingly, foamy macrophages in active multiple sclerosis lesions showed enhanced expression of multidrug resistance-associated protein-1 and breast cancer resistance protein, which coincided with their increased function of cultured foamy macrophages. Strikingly, reactive astrocytes display an increased expression of P-glycoprotein and multidrug resistance-associated protein-1 in both active and inactive multiple sclerosis lesions, which correlated with their enhanced in vitro activity on astrocytes derived from multiple sclerosis lesions. To investigate whether adenosine triphosphate-binding cassette transporters on reactive astrocytes can contribute to the inflammatory process, primary cultures of reactive human astrocytes were generated through activation of Toll-like receptor-3 to mimic the astrocytic phenotype as observed in multiple sclerosis lesions. Notably, blocking adenosine triphosphate-binding cassette transporter activity on reactive astrocytes inhibited immune cell migration across a blood-brain barrier model in vitro, which was due to the reduction of astrocytic release of the chemokine (C-C motif) ligand 2. Our data point towards a novel (patho)physiological role for adenosine triphosphate-binding cassette transporters, suggesting that limiting their activity by dampening astrocyte activation may open therapeutic avenues to diminish tissue damage during multiple sclerosis pathogenesis.
authors.affiliation: Blood-Brain Barrier Research Group, Department of Molecular Cell Biology and Immunology, VU University Medical Centre, Amsterdam, The Netherlands.
authors.forename: Gijs
authors.initials: G
authors.lastname: Kooij
authors.forename: Mark R
authors.initials: MR
authors.lastname: Mizee
authors.forename: Jack
authors.initials: J
authors.lastname: van Horssen
authors.forename: Arie
authors.initials: A
authors.lastname: Reijerkerk
authors.forename: Maarten E
authors.initials: ME
authors.lastname: Witte
authors.forename: Joost A R
authors.initials: JA
authors.lastname: Drexhage
authors.forename: Susanne M A
authors.initials: SM
authors.lastname: van der Pol
authors.forename: Bert
authors.initials: B
authors.lastname: van Het Hof
authors.forename: George
authors.initials: G
authors.lastname: Scheffer
authors.forename: Rik
authors.initials: R
authors.lastname: Scheper
authors.forename: Christine D
authors.initials: CD
authors.lastname: Dijkstra
authors.forename: Paul
authors.initials: P
authors.lastname: van der Valk
authors.forename: Helga E
authors.initials: HE
authors.lastname: de Vries
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001253:Astrocytes / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000502:physiology; D001921:Brain / Q000378:metabolism / Q000503:physiopathology; D018929:Cell Culture Techniques; D002465:Cell Movement / Q000502:physiology; D018932:Chemokine CCL2 / Q000378:metabolism*; D005260:Female; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism / Q000502:physiology; D009103:Multiple Sclerosis / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D018528:ATP-Binding Cassette Transporters; C111835:CCL2 protein, human; D018932:Chemokine CCL2