Intestinal epithelial expression of TNFAIP3 results in microbial invasion of the inner mucus layer and induces colitis in IL-10-deficient mice

Stephen F. Murphy, Lesley Rhee, Wesley A. Grimm, Christopher R. Weber, Jeannette S. Messer, James P. Lodolce, Jonathan E. Chang, Sarah J. Bartulis, Thomas Nero, Renata A. Kukla, Gordon MacDougall, Charles Binghay, Lauren E. Kolodziej, David L. Boone*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)G871-G882
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume307
Issue number9
DOIs
StatePublished - Nov 1 2014

Keywords

  • A20
  • Ang4
  • Intestinal mucus
  • NK-κB
  • Reg3

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology (medical)
  • Physiology
  • Hepatology

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