title: Oxysterols direct immune cell migration via EBI2.
abstract: Epstein-Barr virus-induced gene 2 (EBI2, also known as GPR183) is a G-protein-coupled receptor that is required for humoral immune responses; polymorphisms in the receptor have been associated with inflammatory autoimmune diseases. The natural ligand for EBI2 has been unknown. Here we describe the identification of 7α,25-dihydroxycholesterol (also called 7α,25-OHC or 5-cholesten-3β,7α,25-triol) as a potent and selective agonist of EBI2. Functional activation of human EBI2 by 7α,25-OHC and closely related oxysterols was verified by monitoring second messenger readouts and saturable, high-affinity radioligand binding. Furthermore, we find that 7α,25-OHC and closely related oxysterols act as chemoattractants for immune cells expressing EBI2 by directing cell migration in vitro and in vivo. A critical enzyme required for the generation of 7α,25-OHC is cholesterol 25-hydroxylase (CH25H). Similar to EBI2 receptor knockout mice, mice deficient in CH25H fail to position activated B cells within the spleen to the outer follicle and mount a reduced plasma cell response after an immune challenge. This demonstrates that CH25H generates EBI2 biological activity in vivo and indicates that the EBI2-oxysterol signalling pathway has an important role in the adaptive immune response.
authors.affiliation: Euroscreen S.A., 6041 Gosselies, Belgium.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Hannedouche
authors.forename: Juan
authors.initials: J
authors.lastname: Zhang
authors.forename: Tangsheng
authors.initials: T
authors.lastname: Yi
authors.forename: Weijun
authors.initials: W
authors.lastname: Shen
authors.forename: Deborah
authors.initials: D
authors.lastname: Nguyen
authors.forename: João P
authors.initials: JP
authors.lastname: Pereira
authors.forename: Danilo
authors.initials: D
authors.lastname: Guerini
authors.forename: Birgit U
authors.initials: BU
authors.lastname: Baumgarten
authors.forename: Silvio
authors.initials: S
authors.lastname: Roggo
authors.forename: Ben
authors.initials: B
authors.lastname: Wen
authors.forename: Richard
authors.initials: R
authors.lastname: Knochenmuss
authors.forename: Sophie
authors.initials: S
authors.lastname: Noël
authors.forename: Francois
authors.initials: F
authors.lastname: Gessier
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Kelly
authors.forename: Mirka
authors.initials: M
authors.lastname: Vanek
authors.forename: Stephane
authors.initials: S
authors.lastname: Laurent
authors.forename: Inga
authors.initials: I
authors.lastname: Preuss
authors.forename: Charlotte
authors.initials: C
authors.lastname: Miault
authors.forename: Isabelle
authors.initials: I
authors.lastname: Christen
authors.forename: Ratna
authors.initials: R
authors.lastname: Karuna
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Dong-In
authors.initials: DI
authors.lastname: Koo
authors.forename: Thomas
authors.initials: T
authors.lastname: Suply
authors.forename: Christian
authors.initials: C
authors.lastname: Schmedt
authors.forename: Eric C
authors.initials: EC
authors.lastname: Peters
authors.forename: Rocco
authors.initials: R
authors.lastname: Falchetto
authors.forename: Andreas
authors.initials: A
authors.lastname: Katopodis
authors.forename: Carsten
authors.initials: C
authors.lastname: Spanka
authors.forename: Marie-Odile
authors.initials: MO
authors.lastname: Roy
authors.forename: Michel
authors.initials: M
authors.lastname: Detheux
authors.forename: Yu Alice
authors.initials: YA
authors.lastname: Chen
authors.forename: Peter G
authors.initials: PG
authors.lastname: Schultz
authors.forename: Charles Y
authors.initials: CY
authors.lastname: Cho
authors.forename: Klaus
authors.initials: K
authors.lastname: Seuwen
authors.forename: Jason G
authors.initials: JG
authors.lastname: Cyster
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Sailer
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D001402:B-Lymphocytes; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D006888:Hydroxycholesterols / Q000737:chemistry / Q000494:pharmacology*; D008099:Liver / Q000737:chemistry; D051379:Mice; D018345:Mice, Knockout; D011956:Receptors, Cell Surface / Q000276:immunology*; D043562:Receptors, G-Protein-Coupled; D012756:Sheep; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: C080105:GPR183 protein, human; D006888:Hydroxycholesterols; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C057657:7,25-dihydroxycholesterol