Michel H Maillard1, Hristina Bega, Holm H Uhlig, Nicolas Barnich, Teddy Grandjean, Mathias Chamaillard, Pierre Michetti, Dominique Velin. 1. *Service of Gastroenterology and Hepatology, Department of Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; †Translational Gastroenterology Unit, Division of Experimental Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom; ‡M2iSH, UMR1071 Inserm, Université d'Auvergne, USC-INRA 2018, Clermont-Ferrand, France; §Institut Universitaire de Technologie en Génie Biologique, Aubière, France; ‖Univ Lille Nord de France, Lille, France; ¶Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France; **Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8204, Lille, France; ††Institut National de la Santé et de la Recherche Médicale, U1019, Team 7, Equipe FRM, Lille, France; and ‡‡La Source-Beaulieu, Lausanne, Switzerland.
Abstract
BACKGROUND: The intestinal epithelium accommodates with a myriad of commensals to maintain immunological homeostasis, but the underlying mechanisms regulating epithelial responsiveness to flora-derived signals remain poorly understood. Herein, we sought to determine the role of the Toll/interleukin (IL)-1 receptor regulator Toll-interacting protein (Tollip) in intestinal homeostasis. METHODS: Colitis susceptibility was determined after oral dextran sulfate sodium (DSS) administration or by breeding Tollip on an IL-10 background. The intestinal flora was depleted with 4 antibiotics before DSS exposure to assess its contribution in colitis onset. Bone marrow chimeras were generated to identify the cellular compartment, whereby Tollip may negatively regulate intestinal inflammation in response to DSS. Tollip-dependent epithelial barrier functions were studied in vitro by using Tollip-knockdown in Caco-2 cells and in vivo by immunohistochemistry and fluorescein isothiocyanate-labeled dextran gavage. RESULTS: Genetic ablation of Tollip did not lead to spontaneous intestinal inflammatory disorders. However, Tollip deficiency aggravated spontaneous disease onset in IL-10 mice and increased susceptibility to DSS colitis. Increased colitis severity in Tollip-deficient mice was not improved by bacterial flora depletion using broad-spectrum antibiotics. In addition, DSS exposure of bone marrow chimeric mice revealed a protective role for Tollip in nonhematopoietic cells. Knockdown of Tollip in epithelial cells led to exaggerated NFκ-B activity and proinflammatory cytokine secretion. Finally, DSS-treated Tollip mice showed enhanced intestinal permeability and increased epithelial apoptosis when compared with wild-type controls, a finding that coincided with tight junction alterations on injury. CONCLUSION: Overall, our data show an essential role for Tollip on colitis susceptibility in mice.
BACKGROUND: The intestinal epithelium accommodates with a myriad of commensals to maintain immunological homeostasis, but the underlying mechanisms regulating epithelial responsiveness to flora-derived signals remain poorly understood. Herein, we sought to determine the role of the Toll/interleukin (IL)-1 receptor regulator Toll-interacting protein (Tollip) in intestinal homeostasis. METHODS:Colitis susceptibility was determined after oral dextran sulfate sodium (DSS) administration or by breeding Tollip on an IL-10 background. The intestinal flora was depleted with 4 antibiotics before DSS exposure to assess its contribution in colitis onset. Bone marrow chimeras were generated to identify the cellular compartment, whereby Tollip may negatively regulate intestinal inflammation in response to DSS. Tollip-dependent epithelial barrier functions were studied in vitro by using Tollip-knockdown in Caco-2 cells and in vivo by immunohistochemistry and fluorescein isothiocyanate-labeled dextran gavage. RESULTS: Genetic ablation of Tollip did not lead to spontaneous intestinal inflammatory disorders. However, Tollip deficiency aggravated spontaneous disease onset in IL-10mice and increased susceptibility to DSScolitis. Increased colitis severity in Tollip-deficientmice was not improved by bacterial flora depletion using broad-spectrum antibiotics. In addition, DSS exposure of bone marrow chimeric mice revealed a protective role for Tollip in nonhematopoietic cells. Knockdown of Tollip in epithelial cells led to exaggerated NFκ-B activity and proinflammatory cytokine secretion. Finally, DSS-treated Tollipmice showed enhanced intestinal permeability and increased epithelial apoptosis when compared with wild-type controls, a finding that coincided with tight junction alterations on injury. CONCLUSION: Overall, our data show an essential role for Tollip on colitis susceptibility in mice.
Authors: Alex T Adams; Nicholas A Kennedy; Richard Hansen; Nicholas T Ventham; Kate R OʼLeary; Hazel E Drummond; Colin L Noble; Emad El-Omar; Richard K Russell; David C Wilson; Elaine R Nimmo; Georgina L Hold; Jack Satsangi Journal: Inflamm Bowel Dis Date: 2014-10 Impact factor: 7.290
Authors: Marie Humbert-Claude; D Duc; D Dwir; L Thieren; J Sandström von Tobel; C Begka; F Legueux; D Velin; M H Maillard; K Q Do; F Monnet-Tschudi; L Tenenbaum Journal: J Neuroinflammation Date: 2016-12-07 Impact factor: 8.322