Int J Biol Sci 2020; 16(11):1876-1887. doi:10.7150/ijbs.42331

Research Paper

Slit2/Robo1 Mitigates DSS-induced Ulcerative Colitis by Activating Autophagy in Intestinal Stem Cell

Jingzhou Xie1#, Li Li1#, Shuhua Deng1#, Jiayuan Chen1, Quliang Gu1, Huanhou Su1, Lijing Wen1, Sheng Wang1, Caixia Lin1, Cuiling Qi1, Qianqian Zhang1, Jiangchao Li1, Xiaodong He1, Weidong Li2,3, Lijing Wang1✉, Lingyun Zheng1✉

1. School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510006, Guangdong, PR China.
2. Institute of Health, Guangdong Pharmaceutical University, Guangzhou 510006, Guangdong, P. R. China.
3. Guangdong Engineering Research Center for Light and Health, Guangdong Pharmaceutical University, Guangzhou 510006, Guangdong, P. R. China.
#These authors contributed equally to this work.

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Citation:
Xie J, Li L, Deng S, Chen J, Gu Q, Su H, Wen L, Wang S, Lin C, Qi C, Zhang Q, Li J, He X, Li W, Wang L, Zheng L. Slit2/Robo1 Mitigates DSS-induced Ulcerative Colitis by Activating Autophagy in Intestinal Stem Cell. Int J Biol Sci 2020; 16(11):1876-1887. doi:10.7150/ijbs.42331. Available from http://www.ijbs.com/v16p1876.htm

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Abstract

Ulcerative colitis (UC) is a recurrent intestinal inflammatory disease. Slit2, a secreted protein, interacts with its receptor Robo1 to regulate the differentiation of intestinal stem cells and participate in inflammation and tumor development. However, whether Slit2/Robo1involved in the pathogenesis of UC is not known. We investigated Slit2/Robo1-mediated UC using a dextran sodium sulfate (DSS)-induced model. Eight-week-old male Slit2-Tg (Slit2 transgene) mice, Robo1/2+/- (Robo1+/- Robo2+/-) mice, and their WT littermates were allocated into two groups: (I) control group (n=10), of mice fed a normal diet and tap water and (II) DSS group (n=10), of mice fed a normal diet and drinking water with 2% DSS for 7 days. Colon tissues were collected and analyzed by qPCR, immunohistochemistry, western blot, and immunofluorescence. Slit2-Tg DSS mice showed less body weight loss, less blood in the stool, and less viscous stool compared to those of WTSlit DSS mice. Robo1/2+/- DSS mice displayed a heavier degree of blood in the stool and a more apparent viscosity of the stool compared to those of WTRobo1/2 DSS mice. Slit2 overexpression maintained Lgr5+ stem cell proliferation in the crypt after DSS treatment, significantly increased the LC3II/I ratio, and slightly stimulated p62 expression in the crypt compared to those of DSS-induced WTSlit mice. Robo1/2 partial knockout reduced the number of Lgr5+ stem cells, decreased the LC3II/I ratio, and markedly increased p62 expression in the crypt compare to those of DSS-treated WTRobo1/2 mice. Our findings suggest that Slit2/Robo1 mediates DSS-induced UC probably by activating the autophagy of Lgr5+ stem cells.

Keywords: Slit2/Robo1 signal, UC, autophagy, Lgr5 stem cells