P077 MTOR-MEDIATED SUPPRESSION OF AUTOPHAGY ACTIVITY IN CX3CR1+ MONONUCLEAR PHAGOCYTES CONTRIBUTES TO INTESTINAL FIBROSIS

Abstract

Intestinal fibrosis is a pathological consequence of excessive myofibroblast proliferation and collagen deposition, frequently seen in Crohn’s disease. It is considered as an excessive repair response to injury and inflammation, but not always to be fully correlated with the severity of inflammation. Therefore it needs a better understanding of underlying mechanisms of hyper-proliferation of myofibroblasts in inflammatory bowel disease. In this study, we found that systemic administration of an mTOR inhibitor rapamycin or specific mTOR deletion in mononuclear phagocytes (CX3CR1+) inhibited expression of IL23 and IL-1, along with reduced intestinal production of IL22 and fibrosis in chronic TNBS fibrosis mouse model. Suppression of IL23 and IL-1 expression upon mTOR inhibition is associated with an elevated autophagy activity. Ablating the autophagy gene Atg7 in CX3CR1Atg7f/f mice increases expression of IL23 and IL-1, leading to increased IL22 expression and fibrosis. Moreover, we demonstrated that IL22 facilitated the transformation of fibroblasts to myofibroblasts. IL22-pre-exposed fibroblasts become more sensitive to fibrotic reaction to TGF through induction of TGFRIII. Thus, priming of fibroblasts by IL22 represents a linchpin of excessive fibrotic response. Altogether, this study elucidated a signaling cascade underlying intestinal fibrosis in which mTOR/autophagy in CX3CR1+ mononuclear phagocytes regulates the expression of intestinal IL23/IL22 to mediate the fibrotic response. Thus, this cascade could be a pivotal target for alleviation of intestinal fibrosis.