Astragalus Polysaccharide Protects Experimental Colitis Through An AhR‐Dependent Autophagy Mechanism
Yi Ying, Li‐yun Song, Wen‐lin Pang, Si‐qi Zhang, Jing‐ze Yu, Peng‐tao Liang, Tian‐gang Li, Yi Sun, Yin‐ying Wang, Jin‐yuan Yan, Zhong‐shan Yang- Pharmacology
Background and Purpose
Disruption of intestinal barriers plays a vital role in the pathogenesis of colitis. The aryl hydrocarbon receptor (AhR) is a recognition sensor that mediates intestinal immune homeostasis and minimizes intestinal inflammation. Autophagy depends on AhR activation and might constitute a therapeutic target for colitis. Astragalus polysaccharide (APS) exerts pharmacological action in colitis; however, the mechanism has not been elucidated. We aimed to determine whether APS protects colitis through AhR‐dependent autophagy.
Experimental Approach
The symptoms of DSS‐induced colitis mice involving intestinal barrier function and inflammatory injury were evaluated after APS administration. Intestinal‐specific Becn1 conditional knockout mice (Becn1 cKO) were constructed and compared to WT mice. Autophagy and the therapeutic function of APS were investigated after the deactivation of AhR. The relationship between APS‐induced AhR and autophagic Becn1 was investigated using a dual luciferase reporter system and ChIP‐qPCR assay. Caco‐2 cells investigated inflammatory response and AhR‐dependent autophagy.
Key Results
APS improved intestinal barrier function in the context of inflammatory injury in the colitis mice. APS triggered autophagic flow, however, knockout of the Becn1 in the gut increased susceptibility to colitis, leading to diminished epithelial barrier function and severe intestinal inflammation, furthermore impairing the protective effects of APS. Mechanistically, APS‐triggered autophagy depends on AhR expression. Activated AhR bound to the promoter Becn1 to operate transcription of genes involved in anti‐inflammation and intestinal barrier repair, while deactivation of AhR correlated with intestinal inflammation and the therapeutic function of APS.
Conclusion and Implications
APS protects colitis mice by targeting autophagy, especially that AhR stimulate the repair of damaged intestinal barrier functions.