Abstract
Intestinal fibrosis is an excessive proliferation of myofibroblasts and deposition of collagen, a condition frequently seen in Crohn’s disease (CD). The mechanism underlying myofibroblast hyper-proliferation in CD needs to be better understood. In this report, we found that mTOR inhibitor rapamycin or mTOR deletion in CX3Cr1+ mononuclear phagocytes inhibits expression of interleukin (IL)−23, accompanied by reduced intestinal production of IL-22 and ameliorated fibrosis in the TNBS-induced fibrosis mouse model. This inhibition of IL-23 expression is associated with elevated autophagy activity. Ablating the autophagy gene Atg7 increases the expression of IL-23, leading to increased expression of IL-22 and increased fibrosis. Both induction of IL-22 and intestinal fibrosis occurred in RAG−/− mice and depletion of innate lymphoid cells (ILCs) attenuates the fibrotic reaction, suggesting that the pro-fibrotic process is independent of T and B cells. Moreover, IL-22 facilitates the transformation of fibroblasts into myofibroblasts. Finally, the fibrotic reaction was attenuated upon neutralization of either IL-23 or IL-22. Altogether, this study elucidated a signaling cascade underlying intestinal fibrosis in which altered mTOR/autophagy in CX3Cr1+ mononuclear phagocytes up-regulates the IL-23/IL-22 axis, leading to an excessive fibrotic response. Thus, our findings suggest that this cascade could be a therapeutic target for alleviation of CD fibrosis.
Highlights
Intestinal fibrosis is a severe complication of inflammatory bowel diseases (IBDs) such as Crohn’s disease (CD), and is commonly revealed as intestinal stricture or stenosis.[1]
Here we revealed that the IL-23/IL-22 axis is up regulated in human Crohn’s patients and in the TNBS model of intestinal fibrosis in both wild-type and Rag−/− mice
We further demonstrated that deletion of Atg[7] in these phagocytes exacerbates the induction of IL-23/IL-22 in both the intestine and purified mononuclear phagocytes of TNBS-treated mice
Summary
Intestinal fibrosis is a severe complication of inflammatory bowel diseases (IBDs) such as Crohn’s disease (CD), and is commonly revealed as intestinal stricture or stenosis.[1] Fibrosis gradually evolves in response to prolonged intestinal injury or inflammation, but its manifestation does not necessarily correlate with the severity of inflammation. Fibrosis is generally considered to be irreversible. Despite the advent of new therapeutics (biologics) for IBDs, the incidence of stricture formation and stenosis of the intestine in IBD patients has not improved significantly. Autophagy is a highly conserved catabolic pathway which assists in the sequestration and removal of unwanted cellular debris.[2] Impaired autophagy is associated with the risk of development of CD.[3,4] Genome-wide association studies (GWAS)
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