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Toll-interacting Protein Modulates Colitis Susceptibility in Mice

Maillard, Michel H. MD, PhD*; Bega, Hristina MSc*; Uhlig, Holm H. MD, PhD; Barnich, Nicolas PhD‡,§; Grandjean, Teddy MSc‖,¶,**,††; Chamaillard, Mathias PhD‖,¶,**,††; Michetti, Pierre MD*,‡‡; Velin, Dominique PhD*

doi: 10.1097/MIB.0000000000000006
Original Basic Science Articles

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.

Article first Published online 25 February 2014

*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.

Reprints: Michel H. Maillard, MD, PhD, Service of Gastroenterology and Hepatology, Department of Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, CHUV-BH10, Rue du Bugnon 46, 1011 Lausanne, Switzerland (e-mail: michel.maillard@chuv.ch).

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.ibdjournal.org).

Funding was provided by the European Crohn's and Colitis Organisation (ECCO), a career development grant from the University of Lausanne and the San Salvatore Foundation to M. H. Maillard, and by the Swiss National Foundation Grant 3200B0-120717 to D. Velin. M. Chamaillard was financially supported by grants from the Fondation pour la Recherche Médicale (Equipe FRM 2009) and the FEDER/Région Nord-Pas-de-Calais.

The authors have no conflicts of interest to disclose.

Received January 06, 2014

Accepted January 21, 2014

© Crohn's & Colitis Foundation of America, Inc.
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