Yunnan Provincial Key Laboratory of Integrated Traditional Chinese and Western Medicine for Chronic Disease in Prevention and Treatment, Yunnan University of Chinese Medicine, Kunming, Yunnan, China.
Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China.
Br J Pharmacol. 2024 Mar;181(5):681-697. doi: 10.1111/bph.16229. Epub 2023 Oct 12.
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. Astragalus polysaccharide (APS) exerts pharmacological actions in colitis; however, the mechanism has not been elucidated. We investigated whether APS protects through AhR-dependent autophagy.
The symptoms of dextran sulfate sodium (DSS)-induced colitis in mice involving intestinal barrier function and inflammatory injury were evaluated after APS administration. Intestinal-specific Becn1 conditional knockout (Becn1 cKO) mice were constructed and compared with wild-type mice. Autophagy and the effects of APS were investigated after the deactivation of AhRs. The relationship between APS-induced AhRs and autophagic Becn1 was investigated using a dual-luciferase reporter system and chromatin immunoprecipitation (ChIP)-quantitative polymerase chain reaction assay. Caco-2 cells were used to investigate inflammatory responses and AhR-dependent autophagy.
APS improved intestinal barrier function in inflammatory injury in colitis mice. APS triggered autophagic flow; however, knockout of Becn1 in the gut increased susceptibility to colitis, leading to diminished epithelial barrier function and severe intestinal inflammation, impairing the protective effects of APS. Mechanistically, APS-triggered autophagy depends on AhR expression. Activated AhR binds 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.
APS protects colitis mice by targeting autophagy, especially as the AhR stimulates the repair of damaged intestinal barrier functions.
肠道屏障的破坏在结肠炎发病机制中起着至关重要的作用。芳香烃受体（AhR）是一种识别传感器，可介导肠道免疫稳态并最大程度地减少肠道炎症。黄芪多糖（APS）在结肠炎中具有药理作用；然而，其机制尚未阐明。我们研究了 APS 是否通过 AhR 依赖性自噬来保护。
在给予 APS 后，评估了葡聚糖硫酸钠（DSS）诱导的结肠炎小鼠的肠道屏障功能和炎症损伤症状。构建了肠道特异性Becn1 条件性敲除（Becn1 cKO）小鼠，并与野生型小鼠进行了比较。在 AhR 失活后，研究了自噬和 APS 的作用。使用双荧光素酶报告系统和染色质免疫沉淀（ChIP）-定量聚合酶链反应（PCR）检测 APS 诱导的 AhR 与自噬 Becn1 之间的关系。使用 Caco-2 细胞研究炎症反应和 AhR 依赖性自噬。
APS 改善了结肠炎小鼠炎症损伤中的肠道屏障功能。APS 触发了自噬流；然而，肠道中 Becn1 的敲除增加了结肠炎的易感性，导致上皮屏障功能减弱和严重的肠道炎症，从而削弱了 APS 的保护作用。从机制上讲，APS 触发的自噬依赖于 AhR 表达。激活的 AhR 与 Becn1 启动子结合，从而启动参与抗炎和肠道屏障修复的基因转录，而 AhR 的失活与肠道炎症和 APS 的治疗功能相关。
APS 通过靶向自噬来保护结肠炎小鼠，特别是 AhR 刺激受损肠道屏障功能的修复。
