DARC shuttles inflammatory chemokines across the blood-brain barrier during autoimmune central nervous system inflammation

Minten, Carsten; Alt, Carsten; Gentner, Melanie; Frei, Elisabeth; Deutsch, Urban; Lyck, Ruth; Schaeren-Wiemers, Nicole; Rot, Antal; Engelhardt, Britta (2014). DARC shuttles inflammatory chemokines across the blood-brain barrier during autoimmune central nervous system inflammation. Brain, 137(Pt 5), pp. 1454-1469. Oxford University Press 10.1093/brain/awu045

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Theodor Kocher Institute

UniBE Contributor:

Frei, Elisabeth; Deutsch, Urban; Lyck, Ruth and Engelhardt, Britta

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0006-8950

Publisher:

Oxford University Press

Language:

English

Submitter:

Ursula Zingg-Zünd

Date Deposited:

07 Apr 2015 12:51

Last Modified:

27 Apr 2018 10:44

Publisher DOI:

10.1093/brain/awu045

PubMed ID:

24625696

Uncontrolled Keywords:

DARC, chemokines, blood–brain barrier, multiple sclerosis, experimental autoimmune encephalomyelitis

BORIS DOI:

10.7892/boris.66354

URI:

https://boris.unibe.ch/id/eprint/66354

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