Journal
ACTA PHARMACOLOGICA SINICA
Volume 43, Issue 6, Pages 1495-1507Publisher
NATURE PUBL GROUP
DOI: 10.1038/s41401-021-00781-7
Keywords
ulcerative colitis; baicalein; epithelial barrier; group 3 innate lymphoid cells; interleukin-22; aryl hydrocarbon receptor; CH223191; FICZ
Funding
- National Natural Science Foundation of China [82074092]
- Characteristic Innovation Project of Guangdong Provincial Universities [2020KTSCX026]
- Double First-class and High-level University Discipline Collaborative Innovation Team Project of Guangzhou University of Chinese Medicine [2021xk81]
- Natural Science Foundation of Guangdong Province [2021A1515012219]
- Guangdong Provincial Bureau of Traditional Chinese Medicine [20181076]
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This study elucidates the molecular mechanisms underlying the protective effect of baicalein on intestinal barrier function in colitis mice, demonstrating that baicalein improves gut inflammation, reduces intestinal permeability, and restores tight junctions possibly via promoting AhR/IL-22 pathway. Co-administration of AhR antagonist CH223191 partially blocks the therapeutic effects of baicalein, while AhR agonist FICZ ameliorates symptoms and gut barrier function in colitis mice.
Ulcerative colitis (UC) is a chronic inflammatory disease of the gastrointestinal tract, which is closely related to gut barrier dysfunction. Emerging evidence shows that interleukin-22 (IL-22) derived from group 3 innate lymphoid cells (ILC3s) confers benefits on intestinal barrier, and IL-22 expression is controlled by aryl hydrocarbon receptor (AhR). Previous studies show that baicalein protects the colon from inflammatory damage. In this study we elucidated the molecular mechanisms underlying the protective effect of baicalein on intestinal barrier function in colitis mice. Mice were administered baicalein (10, 20, 40 mg center dot kg(-1)center dot d(-1), i.g.) for 10 days; the mice freely drank 3% dextran sulfate sodium (DSS) on D1-D7 to induce colitis. We showed that baicalein administration simultaneously ameliorated gut inflammation, decreased intestinal permeability, restored tight junctions of colons possibly via promoting AhR/IL-22 pathway. Co-administration of AhR antagonist CH223191 (10 mg/kg, i.p.) partially blocked the therapeutic effects of baicalein in colitis mice, whereas AhR agonist FICZ (1 mu g, i.p.) ameliorated symptoms and gut barrier function in colitis mice. In a murine lymphocyte line MNK-3, baicalein (5-20 mu M) dose-dependently increased the expression of AhR downstream target protein CYP1A1, and enhanced IL-22 production through facilitating AhR nuclear translocation, these effects were greatly diminished in shAhR-MNK3 cells, suggesting that baicalein induced IL-22 production in AhR-dependent manner. To further clarify that, we constructed an in vitro system consisting of MNK-3 and Caco-2 cells, in which MNK-3 cell supernatant treated with baicalein could decrease FITC-dextran permeability and promoted the expression of tight junction proteins ZO-1 and occluding in Caco-2 cells. In conclusion, this study demonstrates that baicalein ameliorates colitis by improving intestinal epithelial barrier via AhR/IL-22 pathway in ILC3s, thus providing a potential therapy for UC.
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