title: Lack of chemokine receptor CCR5 promotes murine fulminant liver failure by preventing the apoptosis of activated CD1d-restricted NKT cells.
abstract: Fulminant liver failure (FLF) consists of a cascade of events beginning with a presumed uncontrolled systemic activation of the immune system. The etiology of FLF remains undefined. In this study, we demonstrate that CCR5 deficiency promotes the development of acute FLF in mice following Con A administration by preventing activated hepatic CD1d-restricted NKT cells (but not conventional T cells) from dying from activation-induced apoptosis. The resistance of CCR5-deficient NKT cells from activation-induced apoptosis following Con A administration is not due to a defective Fas-driven death pathway. Moreover, FLF in CCR5-deficient mice also correlated with hepatic CCR5-deficient NKT cells, producing more IL-4, but not IFN-gamma, relative to wild-type NKT cells. Furthermore, FLF in these mice was abolished by IL-4 mAb or NK1.1 mAb treatment. We propose that CCR5 deficiency may predispose individuals to the development of FLF by preventing hepatic NKT cell apoptosis and by regulating NKT cell function, establishing a novel role for CCR5 in the development of this catastrophic liver disease that is independent of leukocyte recruitment.
authors.affiliation: Gastrointestinal Research Group, Diabetes and Endocrine Research Group, and Department of Histopathology, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Maureen N
authors.initials: MN
authors.lastname: Ajuebor
authors.forename: Alex I
authors.initials: AI
authors.lastname: Aspinall
authors.forename: Feng
authors.initials: F
authors.lastname: Zhou
authors.forename: Tai
authors.initials: T
authors.lastname: Le
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Urbanski
authors.forename: Stéphané
authors.initials: S
authors.lastname: Sidobre
authors.forename: Mitchell
authors.initials: M
authors.lastname: Kronenberg
authors.forename: Cory M
authors.initials: CM
authors.lastname: Hogaboam
authors.forename: Mark G
authors.initials: MG
authors.lastname: Swain
mesh_terms: D000818:Animals; D018949:Antigens, CD1 / Q000502:physiology*; D055610:Antigens, CD1d; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D003208:Concanavalin A / Q000008:administration & dosage; D007113:Immunity, Innate / Q000235:genetics; D015847:Interleukin-4 / Q000096:biosynthesis / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D017114:Liver Failure, Acute / Q000235:genetics / Q000276:immunology* / Q000473:pathology* / Q000517:prevention & control; D008213:Lymphocyte Activation / Q000235:genetics; D008212:Lymphocyte Depletion / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019713:Receptors, CCR5 / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019014:fas Receptor / Q000096:biosynthesis / Q000502:physiology
chemical_list: D018949:Antigens, CD1; D055610:Antigens, CD1d; D019713:Receptors, CCR5; D019014:fas Receptor; D003208:Concanavalin A; D015847:Interleukin-4