Role of Grail in intestinal inflammation

Abstract

Abstract Intestinal homeostasis depends on interaction between the microbiota and host immune system, and disruption of this balance results in predominance of inflammatory responses leading to inflammatory bowel disease. However, to date, precise cell-intrinsic regulatory mechanisms that controls intestinal inflammation are poorly understood. Here we show that expression of the E3 ubiquitin ligase Grail is diminished in colon tissues of mice with colitis and Grail deficiency leads to increased susceptibility to colitis. Importantly, Grail deficiency disrupted pro-/anti-inflammatory balance towards inflammatory immune responses at the steady state and during colitis. Mechanistically, loss of Grail intrinsically diminished the expression of IL-10 and IL-10 receptor (IL-10R) by adaptive and innate immune cells in colonic mucosa. Besides the intestinal immunity, Grail deficiency leads to a decrease in microbial diversity and an enrichment of pro-inflammatory microbiota. Thus, Grail plays a protective role during intestinal inflammation by supporting regulatory immune responses and shaping the microbiota.