A20 controls intestinal homeostasis through cell-specific activities

Lars Vereecke, Sara Vieira-Silva, Thomas Billiet, Johan H van Es, Conor Mc Guire, Karolina Slowicka, Mozes Sze, Maaike van den Born, Gert De Hertogh, Hans Clevers, Jeroen Raes, Paul Rutgeerts, Severine Vermeire, Rudi Beyaert, Geert van Loo

Research output: Contribution to journal/periodicalArticleScientificpeer-review

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.

Original languageEnglish
Pages (from-to)5103
JournalNature Communications
Volume5
DOIs
Publication statusPublished - 2014

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    Vereecke, L., Vieira-Silva, S., Billiet, T., van Es, J. H., Mc Guire, C., Slowicka, K., Sze, M., van den Born, M., De Hertogh, G., Clevers, H., Raes, J., Rutgeerts, P., Vermeire, S., Beyaert, R., & van Loo, G. (2014). A20 controls intestinal homeostasis through cell-specific activities. Nature Communications, 5, 5103. https://doi.org/10.1038/ncomms6103