Markus Tschurtschenthaler1, Jun Wang2, Cornelia Fricke3, Teresa M J Fritz3, Lukas Niederreiter4, Timon E Adolph4, Edina Sarcevic5, Sven Künzel6, Felix A Offner5, Ulrich Kalinke7, John F Baines2, Herbert Tilg8, Arthur Kaser9. 1. Division of Gastroenterology & Hepatology, Department of Medicine, University of Cambridge, Cambridge, UK Department of Medicine I, Innsbruck Medical University, Innsbruck, Austria. 2. Max Planck Institute for Evolutionary Biology, Plön, Germany Institute for Experimental Medicine, Christian-Albrechts-University of Kiel, Kiel, Germany. 3. Department of Medicine II, Innsbruck Medical University, Innsbruck, Austria. 4. Division of Gastroenterology & Hepatology, Department of Medicine, University of Cambridge, Cambridge, UK. 5. Department of Pathology, Academic Teaching Hospital Feldkirch, Feldkirch, Austria. 6. Max Planck Institute for Evolutionary Biology, Plön, Germany. 7. Division of Immunology, Paul-Ehrlich-Institute, Langen, Germany. 8. Department of Medicine I, Innsbruck Medical University, Innsbruck, Austria Christian-Doppler Research Laboratory for Gut Inflammation, Innsbruck Medical University, Innsbruck, Austria. 9. Division of Gastroenterology & Hepatology, Department of Medicine, University of Cambridge, Cambridge, UK Department of Medicine II, Innsbruck Medical University, Innsbruck, Austria.
Abstract
OBJECTIVE: Intestinal epithelial cells (IECs) at the internal/external interface orchestrate the mucosal immune response. Paneth cells secrete antimicrobial peptides and inflammatory mediators, protect from pathogens and shape the commensal microbiota. Prompted by the genetic association of the locus harbouring the type I interferon (IFN) receptor (IFNAR1) with Crohn's disease, and a transcriptional signature for type I IFN signalling in Paneth cells, we studied the function of IFNAR1 in IECs. DESIGN: Type I IFN signalling was studied in mice with conditional deletion of Ifnar1 in IECs. Phenotype was characterised at baseline, and gut microbiota composition was assessed by 16S rDNA ribotyping. The role of IFNAR1 was also investigated in experimental colitis induced by dextran sodium sulfate (DSS) and colitis-associated cancer induced by DSS in conjunction with azoxymethane (AOM). RESULTS: Ifnar1(-/-(IEC)) mice displayed expansion of Paneth cell numbers and epithelial hyperproliferation compared with Ifnar1-sufficient littermates. While Ifnar1(-/-(IEC)) mice did not exhibit spontaneous inflammation or increased severity in DSS colitis compared with Ifnar1(+/+(IEC)) mice, they exhibited an increased tumour burden in the AOM/DSS model. Both hyperproliferation and tumour promotion were dependent on the microbial flora, as the differences between genotypes were marked upon separately housing mice, but disappeared when Ifnar1(-/-(IEC)) and Ifnar1(+/+(IEC)) mice were co-housed. Accordingly, ribotyping revealed marked differences between Ifnar1(-/-(IEC)) and Ifnar1(+/+(IEC)) mice that where diminished upon co-housing. CONCLUSIONS: IFNAR1 in IECs, and Paneth cells in particular, contributes to the regulation of the host-microbiota relationship, with consequences for intestinal regeneration and colitis-associated tumour formation. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
OBJECTIVE: Intestinal epithelial cells (IECs) at the internal/external interface orchestrate the mucosal immune response. Paneth cells secrete antimicrobial peptides and inflammatory mediators, protect from pathogens and shape the commensal microbiota. Prompted by the genetic association of the locus harbouring the type I interferon (IFN) receptor (IFNAR1) with Crohn's disease, and a transcriptional signature for type I IFN signalling in Paneth cells, we studied the function of IFNAR1 in IECs. DESIGN: Type I IFN signalling was studied in mice with conditional deletion of Ifnar1 in IECs. Phenotype was characterised at baseline, and gut microbiota composition was assessed by 16S rDNA ribotyping. The role of IFNAR1 was also investigated in experimental colitis induced by dextran sodium sulfate (DSS) and colitis-associated cancer induced by DSS in conjunction with azoxymethane (AOM). RESULTS: Ifnar1(-/-(IEC)) mice displayed expansion of Paneth cell numbers and epithelial hyperproliferation compared with Ifnar1-sufficient littermates. While Ifnar1(-/-(IEC)) mice did not exhibit spontaneous inflammation or increased severity in DSS colitis compared with Ifnar1(+/+(IEC)) mice, they exhibited an increased tumour burden in the AOM/DSS model. Both hyperproliferation and tumour promotion were dependent on the microbial flora, as the differences between genotypes were marked upon separately housing mice, but disappeared when Ifnar1(-/-(IEC)) and Ifnar1(+/+(IEC)) mice were co-housed. Accordingly, ribotyping revealed marked differences between Ifnar1(-/-(IEC)) and Ifnar1(+/+(IEC)) mice that where diminished upon co-housing. CONCLUSIONS: IFNAR1 in IECs, and Paneth cells in particular, contributes to the regulation of the host-microbiota relationship, with consequences for intestinal regeneration and colitis-associated tumour formation. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Authors: Yuliya V Katlinskaya; Kanstantsin V Katlinski; Audrey Lasri; Ning Li; Daniel P Beiting; Amy C Durham; Ting Yang; Eli Pikarsky; Christopher J Lengner; F Brad Johnson; Yinon Ben-Neriah; Serge Y Fuchs Journal: Mol Cell Biol Date: 2016-01-25 Impact factor: 4.272
Authors: J Brasseit; E Althaus-Steiner; M Faderl; N Dickgreber; L Saurer; V Genitsch; T Dolowschiak; H Li; D Finke; W-D Hardt; K D McCoy; A J Macpherson; N Corazza; M Noti; C Mueller Journal: Mucosal Immunol Date: 2015-09-16 Impact factor: 7.313