title: TNF-alpha-secreting monocytes are recruited into the brain of cholestatic mice.
abstract: Signaling occurs between the liver and brain in cholestatic liver disease, giving rise to sickness behaviors such as fatigue. However, the signaling pathways involved are poorly defined. Circulating inflammatory mediator levels are increased in cholestasis, leading to speculation that they may be capable of activating circulating immune cells that subsequently could gain access to the brain. Indeed, we have identified that at day 10 after bile duct resection-induced cholestasis, there is activation of circulating monocytes that express tumor necrosis factor alpha (TNF-alpha) in conjunction with increased expression of adhesion molecules by cerebral endothelium. Moreover, using intravital microscopy, we have identified markedly enhanced leukocytes rolling along cerebral endothelial cells, mediated by P-selectin, in bile duct-resected (BDR) but not control mice. In addition, we have identified increased infiltration of monocytes (but not lymphocytes) into the brains of BDR mice and found that these infiltrating monocytes produce TNF-alpha. Furthermore, infiltration of TNF-alpha-secreting monocytes into the brains of cholestatic mice is associated with a broad activation of resident brain macrophages to produce TNF-alpha. In conclusion, cholestasis is associated with an activation of cerebral endothelium that recruits TNF-alpha-producing monocytes into the brain. We hypothesize that enhanced TNF-alpha release within the brain may contribute to the development of cholestasis-associated sickness behaviors, including fatigue.
authors.affiliation: Immunology Research Group, Health Sciences Center, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Kerfoot
authors.forename: Charlotte
authors.initials: C
authors.lastname: D'Mello
authors.forename: Henry
authors.initials: H
authors.lastname: Nguyen
authors.forename: Maureen N
authors.initials: MN
authors.lastname: Ajuebor
authors.forename: Paul
authors.initials: P
authors.lastname: Kubes
authors.forename: Tai
authors.initials: T
authors.lastname: Le
authors.forename: Mark G
authors.initials: MG
authors.lastname: Swain
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply / Q000276:immunology* / Q000473:pathology; D002465:Cell Movement; D002779:Cholestasis / Q000150:complications / Q000276:immunology*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000502:physiology; D005221:Fatigue / Q000209:etiology*; D036904:Leukocyte Rolling; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
chemical_list: D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1