6-姜烯酚上调IL-22减轻放射性肠损伤的机制研究

Intestinal stem cells are surprisingly sensitive to ionizing radiation. Radiation enteritis is a common complication of radiotherapy and Radiation accidents caused by impaired intestinal stem cells, and subsequent loss of the mucosal barrier. In the previous experiment, we found that 6-shogaol, the supercritical extraction of ginger, can protect the intestinal injury including reducing the intestinal inflammation and mucosal barrier damage following abdominal irradiation, but the mechanism remains unclear. Previous studies have shown that IL-22 plays an important role in the regulation of intestinal inflammation, tissue regeneration and mucosal barrier in inflammatory bowel disease. We further found that 6-shogaol induce the expression of anti-inflammatory factor IL-22 in intestinal tissue. The results suggested that 6-shogaol may protect radiation-induced injury via upregulation of IL-22. After 6-shogaol treatment and suppressing IL-22 level in the mice model of intestinal radiation injury, we intend to clarify the role of IL-22 in the 6-shogaol protection of Intestinal radiation injury by the changes of the mucosal barrier, mucosal immunity, and stem cell regeneration. Further experiments in vivo, we try to explore the cellular sources of IL-22 after 6-shogaol with the αThy-1 antibody inhibits the extravasation of leukocytes into the lamina propria, therefore to provide a theoretical basis for 6-shogaol as a radiation protection strategy that promotes IL-22 secretion.

由于肠干细胞对电离辐射极为敏感，受照者往往因肠干细胞受损导致粘膜屏障破坏引起放射性肠炎。既往研究表明，IL-22对调节肠道炎症，组织再生，粘膜完整性有着重要作用。我们前期研究发现，从生姜中超临界萃取的6-姜烯酚对腹部照射引起的放射性肠损伤具有防护作用，减轻了放射引起的肠道炎症和粘膜屏障破坏，同时促进了肠道组织中抗炎因子IL-22的表达，提示6-姜烯酚可能通过促进IL-22分泌发挥辐射防护作用。本课题拟在小鼠放射性肠损伤模型和肠类器官模型中，通过6-姜烯酚和抑制IL-22水平处理后，检测肠道屏障，肠道免疫和干细胞再生能力，明确6-姜烯酚是否通促进IL-22分泌作用发挥放射性肠损伤中的防护作用；此外，通过aThy-1抗体抑制白细胞迁移到肠道固有层，通过流式细胞术，探索6-姜烯酚诱导肠道中分泌IL-22的细胞来源，为新的辐射防护药物的研发奠定基础。

由于肠干细胞对电离辐射极为敏感，受照者往往因肠干细胞受损导致粘膜屏障破坏引起放射性肠炎。既往研究表明，IL-22对调节肠道炎症，组织再生，粘膜完整性有着重要作用。我们前期研究发现，从生姜中超临界萃取的6-姜烯酚对腹部照射引起的放射性肠损伤具有防护作用，减轻了放射引起的肠道炎症和粘膜屏障破坏，同时促进了肠道组织中抗炎因子IL-22的表达，提示6-姜烯酚可能通过促进IL-22分泌发挥辐射防护作用。本研究中首先通过转录组测序发现放射性肠损伤中肠道组织对辐射后损伤响应，聚焦在肠道免疫功能减弱的现象，尤其是IL-22水平下降导致的后续生物学功能的改变；进而，发现IL-22水平下降的机制与Ahr信号通路的激活相关；因此，采用6-shogaol作为Ahr的天然产物的激活剂，促进Ahr信号通路的激活，上调IL-22细胞因子；最后，确定6-shogaol促进IL-22上调的细胞来源，其发挥了维持肠道面膜完整性，起到辐射防护作用，为新的辐射防护药物的研发奠定基础。