title: Loss of vagal anti-inflammatory effect: in vivo visualization and adoptive transfer.
abstract: The vagus nerve is a conduit for bidirectional signaling between the brain and the viscera. Vagal signaling has been shown to downregulate gastrointestinal inflammation, and the mechanism is thought to involve acetylcholine binding to the alpha-7 subunit of the nicotinic acetylcholine receptor on macrophages. The aims of this study were to quantify the impact of vagotomy in vivo by visualizing nuclear factor (NF)-kappaB activity and to determine if the proinflammatory impact of vagotomy could be transferred by lymphocytes. Real-time biophotonic imaging revealed that subdiaphragmatic vagotomy resulted in increased levels of NF-kappaB in vivo. NF-kappaB activation was further exaggerated in vivo following exposure to 4% DSS for 5 days. Vagotomized animals also exhibited higher disease activity scores and secreted more proinflammatory cytokines. Adoptive transfer of CD4(+) T cells from vagotomized animals (but not CD4(+) T cells from sham-operated controls) to naive dextran sulfate sodium (DSS)-treated recipients resulted in increased inflammatory scores. Further examination of the CD4(+) T cells revealed that adoptive transfer of the CD25(-) population alone from vagotomized donors (but not sham-operated donors) was sufficient to aggravate colitis in DSS-treated recipients. Increased DSS-induced inflammation was associated with reduced CD4(+)CD25(+)Foxp3(+) regulatory T cell numbers in recipients. This study clearly demonstrates the ability of the vagus nerve to modulate activity of the proinflammatory transcription factor NF-kappaB in vivo. The proinflammatory effect of vagotomy is transferable using splenic T cells and highlights a previously unappreciated cellular mechanism for linking central parasympathetic processes with mucosal inflammation and immune homeostasis.
authors.affiliation: Alimentary Pharmabiotic Centre, National University of Ireland, Cork, Ireland.
authors.forename: Caitlin
authors.initials: C
authors.lastname: O'Mahony
authors.forename: Hanneke
authors.initials: H
authors.lastname: van der Kleij
authors.forename: John
authors.initials: J
authors.lastname: Bienenstock
authors.forename: Fergus
authors.initials: F
authors.lastname: Shanahan
authors.forename: Liam
authors.initials: L
authors.lastname: O'Mahony
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D003092:Colitis / Q000139:chemically induced / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D003106:Colon / Q000276:immunology / Q000294:innervation*; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000032:analysis; D017930:Genes, Reporter; D018836:Inflammation Mediators / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D049409:Luciferases, Firefly / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000637:transplantation*; D014628:Vagotomy; D014630:Vagus Nerve / Q000503:physiopathology* / Q000601:surgery; D051598:Whole Body Imaging
chemical_list: D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C508018:Il2ra protein, mouse; D018836:Inflammation Mediators; D053645:Interleukin-2 Receptor alpha Subunit; D016328:NF-kappa B; D016264:Dextran Sulfate; D049409:Luciferases, Firefly