title: Vagal innervation is required for the formation of tertiary lymphoid tissue in colitis.
abstract: Tertiary lymphoid tissue (TLT) is lymphoid tissue that forms in adult life as a result of chronic inflammation in a tissue or organ. TLT has been shown to form in a variety of chronic inflammatory diseases, though it is not clear if and how TLT develops in the inflamed colon during inflammatory bowel disease. Here, we show that TLT develops as newly formed lymphoid tissue in the colon following dextran sulphate sodium induced colitis in C57BL/6 mice, where it can be distinguished from the preexisting colonic patches and solitary intestinal lymphoid tissue. TLT in the inflamed colon develops following the expression of lymphoid tissue-inducing chemokines and adhesion molecules, such as CXCL13 and VCAM-1, respectively, which are produced by stromal organizer cells. Surprisingly, this process of TLT formation was independent of the lymphotoxin signaling pathway, but rather under neuronal control, as we demonstrate that selective surgical ablation of vagus nerve innervation inhibits CXCL13 expression and abrogates TLT formation without affecting colitis. Sympathetic neuron denervation does not affect TLT formation. Hence, we reveal that inflammation in the colon induces the formation of TLT, which is controlled by innervation through the vagus nerve.
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.|Department of Molecular Cell Biology and Immunology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.|Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, ,University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Brenda J
authors.initials: BJ
authors.lastname: Olivier
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Cathy
authors.initials: C
authors.lastname: Cailotto
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: van der Vliet
authors.affiliation: Department of Molecular Cell Biology and Immunology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
authors.forename: Marlene
authors.initials: M
authors.lastname: Knippenberg
authors.affiliation: Department of Molecular Cell Biology and Immunology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
authors.forename: Mascha J
authors.initials: MJ
authors.lastname: Greuter
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Francisca W
authors.initials: FW
authors.lastname: Hilbers
authors.affiliation: Department of Molecular Cell Biology and Immunology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
authors.forename: Tanja
authors.initials: T
authors.lastname: Konijn
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Anje A
authors.initials: AA
authors.lastname: Te Velde
authors.affiliation: Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, ,University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Martijn A
authors.initials: MA
authors.lastname: Nolte
authors.affiliation: Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Department of Gastroenterology, University Hospital Leuven, Leuven, Belgium.
authors.forename: Guy E
authors.initials: GE
authors.lastname: Boeckxstaens
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands. w.j.dejonge@amc.uva.nl.
authors.forename: Wouter J
authors.initials: WJ
authors.lastname: de Jonge
authors.affiliation: Department of Molecular Cell Biology and Immunology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.
authors.forename: Reina E
authors.initials: RE
authors.lastname: Mebius
mesh_terms: D000818:Animals; D054382:Chemokine CXCL13 / Q000235:genetics / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000276:immunology*; D003106:Colon / Q000294:innervation* / Q000473:pathology; D016264:Dextran Sulfate; D005260:Female; D008221:Lymphoid Tissue / Q000294:innervation* / Q000473:pathology; D008233:Lymphotoxin-alpha / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction; D000072717:Tertiary Lymphoid Structures / Q000473:pathology*; D014630:Vagus Nerve / Q000473:pathology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D054382:Chemokine CXCL13; C486386:Cxcl13 protein, mouse; D008233:Lymphotoxin-alpha; D019010:Vascular Cell Adhesion Molecule-1; D016264:Dextran Sulfate
keywords: Chemokines; Dextran sodium sulphate colitis model; Stromal cells; Tertiary lymphoid tissue; Vagus nerve