title: DARC shuttles inflammatory chemokines across the blood-brain barrier during autoimmune central nervous system inflammation.
abstract: The Duffy antigen/receptor for chemokines, DARC, belongs to the family of atypical heptahelical chemokine receptors that do not couple to G proteins and therefore fail to transmit conventional intracellular signals. Here we show that during experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, the expression of DARC is upregulated at the blood-brain barrier. These findings are corroborated by the presence of a significantly increased number of subcortical white matter microvessels staining positive for DARC in human multiple sclerosis brains as compared to control tissue. Using an in vitro blood-brain barrier model we demonstrated that endothelial DARC mediates the abluminal to luminal transport of inflammatory chemokines across the blood-brain barrier. An involvement of DARC in experimental autoimmune encephalomyelitis pathogenesis was confirmed by the observed ameliorated experimental autoimmune encephalomyelitis in Darc(-/-) C57BL/6 and SJL mice, as compared to wild-type control littermates. Experimental autoimmune encephalomyelitis studies in bone marrow chimeric Darc(-/-) and wild-type mice revealed that increased plasma levels of inflammatory chemokines in experimental autoimmune encephalomyelitis depended on the presence of erythrocyte DARC. However, fully developed experimental autoimmune encephalomyelitis required the expression of endothelial DARC. Taken together, our data show a role for erythrocyte DARC as a chemokine reservoir and that endothelial DARC contributes to the pathogenesis of experimental autoimmune encephalomyelitis by shuttling chemokines across the blood-brain barrier.
authors.affiliation: 1 Theodor Kocher Institute, University of Bern, CH-3012 Bern, Switzerland.
authors.forename: Carsten
authors.initials: C
authors.lastname: Minten
authors.forename: Carsten
authors.initials: C
authors.lastname: Alt
authors.forename: Melanie
authors.initials: M
authors.lastname: Gentner
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Frei
authors.forename: Urban
authors.initials: U
authors.lastname: Deutsch
authors.forename: Ruth
authors.initials: R
authors.lastname: Lyck
authors.forename: Nicole
authors.initials: N
authors.lastname: Schaeren-Wiemers
authors.forename: Antal
authors.initials: A
authors.lastname: Rot
authors.forename: Britta
authors.initials: B
authors.lastname: Engelhardt
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D015703:Antigens, CD / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000503:physiopathology; D002199:Capillary Permeability / Q000235:genetics; D002490:Central Nervous System / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002531:Cerebellum / Q000378:metabolism; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004375:Duffy Blood-Group System / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000097:blood / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D066298:In Vitro Techniques; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000473:pathology; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: D015703:Antigens, CD; D018925:Chemokines; D004375:Duffy Blood-Group System; D011956:Receptors, Cell Surface; C483025:Ackr1 protein mouse
keywords: DARC; blood–brain barrier; chemokines; experimental autoimmune encephalomyelitis; multiple sclerosis