A20/TNFAIP3: Master Regulator of Intestinal Immune Homeostasis

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. Using tissue specific A20 knockout mice, we dissected the contribution of A20 to maintaining intestinal immune homeostasis. 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. However, myeloid specific A20 knockout mice do not spontaneously develop intestinal pathology and are strongly protected in experimental colitis models. The pro-inflammatory environment in myeloid specific A20 knockout mice induces strong expansion of ‘myeloid derived suppressor cells’ (MDSCs) which suppress both innate and adaptive immunity in a tissue dependent manner. Although A20 defects are associated with multiple human inflammatory and auto-immune pathologies, myeloid-specific A20 deficiency results in protection from colitis. These studies underscore the delicate role of A20 in balancing intestinal immunity.