title: Intestinal epithelial expression of TNFAIP3 results in microbial invasion of the inner mucus layer and induces colitis in IL-10-deficient mice.
abstract: Tumor necrosis factor-induced protein 3 (TNFAIP3; also known as A20) negatively regulates NF-κB and MAPK signals to control inflammatory responses. TNFAIP3 also protects against TNF-induced cell death. Intestinal epithelial cell (IEC) expression of TNFAIP3 improves barrier function and tight junction integrity and prevents dextran sulfate sodium (DSS)-induced IEC death and colitis. We therefore investigated the effects of TNFAIP3 expression in IEC on immune homeostasis in the intestines of immune-compromised mice. Villin-TNFAIP3 (v-TNFAIP3) transgenic mice were interbred with IL-10(-/-) mice (v-TNFAIP3 × IL-10(-/-)) and incidence, onset, and severity of colitis was assessed. v-TNFAIP3 × IL-10(-/-) mice displayed severe, early onset, and highly penetrant colitis that was not observed in IL-10(-/-) or v-TNFAIP3 mice. V-TNFAIP3 mice displayed altered expression of mucosal cytokines, increased numbers of mucosal regulatory T cells, and altered expression of mucosal antimicrobial peptides (AMPs). Microbial colonization of the inner mucus layer of v-TNFAIP3 mice was observed, along with alterations in the microbiome, but this was not sufficient to induce colitis in v-TNFAIP3 mice. The relative sterility of the inner mucus layer observed in wild-type and IL-10(-/-) mice was lost in v-TNFAIP3 × IL-10(-/-) mice. Thus IEC-derived factors, induced by signals that are inhibited by TNFAIP3, suppress the onset of inflammatory bowel disease in IL-10(-/-) mice. Our results indicate that IEC expression of TNFAIP3 alters AMP expression and allows microbial colonization of the inner mucus layer, which activates an IL-10-dependent anti-inflammatory process that is necessary to prevent colitis.
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois;
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Murphy
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois;
authors.forename: Lesley
authors.initials: L
authors.lastname: Rhee
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois;
authors.forename: Wesley A
authors.initials: WA
authors.lastname: Grimm
authors.affiliation: Department of Pathology, University of Chicago, Chicago, Illinois;
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Weber
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois;
authors.forename: Jeannette S
authors.initials: JS
authors.lastname: Messer
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois;
authors.forename: James P
authors.initials: JP
authors.lastname: Lodolce
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois;
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Chang
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois;
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Bartulis
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois;
authors.forename: Thomas
authors.initials: T
authors.lastname: Nero
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois;
authors.forename: Renata A
authors.initials: RA
authors.lastname: Kukla
authors.affiliation: Indiana University School of Medicine, South Bend, Indiana.
authors.forename: Gordon
authors.initials: G
authors.lastname: MacDougall
authors.affiliation: Indiana University School of Medicine, South Bend, Indiana.
authors.forename: Charles
authors.initials: C
authors.lastname: Binghay
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois;
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Kolodziej
authors.affiliation: Indiana University School of Medicine, South Bend, Indiana daboone@iu.edu.
authors.forename: David L
authors.initials: DL
authors.lastname: Boone
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D003093:Colitis, Ulcerative / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D016753:Interleukin-10 / Q000235:genetics*; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D064307:Microbiota; D000073718:Pancreatitis-Associated Proteins; D012259:Ribonuclease, Pancreatic / Q000235:genetics / Q000378:metabolism; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; C556062:IL10 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D000073718:Pancreatitis-Associated Proteins; D016753:Interleukin-10; C519253:Ang4 protein, mouse; D012259:Ribonuclease, Pancreatic; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse
keywords: A20; Ang4; NK-κB; Reg3; intestinal mucus