title: A20 controls intestinal homeostasis through cell-specific activities.
abstract: The transcription factor NF-κB is indispensable for intestinal immune homeostasis, but contributes to chronic inflammation and inflammatory bowel disease (IBD). A20, an inhibitor of both NF-κB and apoptotic signalling, was identified as a susceptibility gene for multiple inflammatory diseases, including IBD. Despite absence of spontaneous intestinal inflammation in intestinal epithelial cell (IEC) specific A20 knockout mice, we found additional myeloid-specific A20 deletion to synergistically drive intestinal pathology through cell-specific mechanisms. A20 ensures intestinal barrier stability by preventing cytokine-induced IEC apoptosis, while A20 prevents excessive cytokine production in myeloid cells. Combining IEC and myeloid A20 deletion induces ileitis and severe colitis, characterized by IEC apoptosis, Paneth and goblet cell loss, epithelial hyperproliferation and intestinal microbiota dysbiosis. Continuous epithelial cell death and regeneration in an inflammatory environment sensitizes cells for neoplastic transformation and the development of colorectal tumours in aged mice.
authors.affiliation: 1] Unit of Molecular Signal Transduction in Inflammation, Inflammation Research Center, VIB, Technologiepark 927, B-9052 Ghent, Belgium [2] Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, B-9052 Ghent, Belgium.
authors.forename: Lars
authors.initials: L
authors.lastname: Vereecke
authors.affiliation: 1] Department of Microbiology and Immunology, Rega Institute, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium [2] Center for the Biology of Disease, VIB, Herestraat 49, B-3000 Leuven, Belgium [3] Department of Bioscience Engineering (DBIT/MICR), VUB, Pleinlaan 2, B-1050 Brussels, Belgium.
authors.forename: Sara
authors.initials: S
authors.lastname: Vieira-Silva
authors.affiliation: Department of Clinical and Experimental Medicine, TARGID, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Billiet
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research and University Medical Centre Utrecht, Uppsalalaan 8, NL-3584 Utrecht, The Netherlands.
authors.forename: Johan H
authors.initials: JH
authors.lastname: van Es
authors.affiliation: 1] Unit of Molecular Signal Transduction in Inflammation, Inflammation Research Center, VIB, Technologiepark 927, B-9052 Ghent, Belgium [2] Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, B-9052 Ghent, Belgium.
authors.forename: Conor
authors.initials: C
authors.lastname: Mc Guire
authors.affiliation: 1] Unit of Molecular Signal Transduction in Inflammation, Inflammation Research Center, VIB, Technologiepark 927, B-9052 Ghent, Belgium [2] Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, B-9052 Ghent, Belgium.
authors.forename: Karolina
authors.initials: K
authors.lastname: Slowicka
authors.affiliation: 1] Unit of Molecular Signal Transduction in Inflammation, Inflammation Research Center, VIB, Technologiepark 927, B-9052 Ghent, Belgium [2] Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, B-9052 Ghent, Belgium.
authors.forename: Mozes
authors.initials: M
authors.lastname: Sze
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research and University Medical Centre Utrecht, Uppsalalaan 8, NL-3584 Utrecht, The Netherlands.
authors.forename: Maaike
authors.initials: M
authors.lastname: van den Born
authors.affiliation: Department of Morphology and Molecular Pathology, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium.
authors.forename: Gert
authors.initials: G
authors.lastname: De Hertogh
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research and University Medical Centre Utrecht, Uppsalalaan 8, NL-3584 Utrecht, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
authors.affiliation: 1] Department of Microbiology and Immunology, Rega Institute, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium [2] Center for the Biology of Disease, VIB, Herestraat 49, B-3000 Leuven, Belgium [3] Department of Bioscience Engineering (DBIT/MICR), VUB, Pleinlaan 2, B-1050 Brussels, Belgium.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Raes
authors.affiliation: Department of Clinical and Experimental Medicine, TARGID, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium.
authors.forename: Paul
authors.initials: P
authors.lastname: Rutgeerts
authors.affiliation: Department of Clinical and Experimental Medicine, TARGID, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium.
authors.forename: Severine
authors.initials: S
authors.lastname: Vermeire
authors.affiliation: 1] Unit of Molecular Signal Transduction in Inflammation, Inflammation Research Center, VIB, Technologiepark 927, B-9052 Ghent, Belgium [2] Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, B-9052 Ghent, Belgium [3].
authors.forename: Rudi
authors.initials: R
authors.lastname: Beyaert
authors.affiliation: 1] Unit of Molecular Signal Transduction in Inflammation, Inflammation Research Center, VIB, Technologiepark 927, B-9052 Ghent, Belgium [2] Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, B-9052 Ghent, Belgium [3].
authors.forename: Geert
authors.initials: G
authors.lastname: van Loo
mesh_terms: D000818:Animals; D017209:Apoptosis; D003092:Colitis / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000201:enzymology* / Q000473:pathology; D005260:Female; D020397:Goblet Cells / Q000166:cytology / Q000201:enzymology / Q000473:pathology; D006706:Homeostasis; D006801:Humans; D007422:Intestines / Q000201:enzymology* / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019879:Paneth Cells / Q000166:cytology / Q000201:enzymology / Q000473:pathology; D013045:Species Specificity; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse