Intestinal Epithelial Cells-Derived Hypoxia-Inducible Factor-1α Is Essential for the Homeostasis of Intestinal Intraepithelial Lymphocytes

Hif-1α is a master regulator which involved in the transcriptional regulation of anti-inflammatory or cellular responding to hypoxia. Previous work shows that the absence of Hif-1α results in the destruction of intestinal epithelial cell (IEC) and abnormalities of intestinal barrier function. However, we know very little about other functions of Hif-1α on intestinal intraepithelial lymphocyte (IEL). Therefore, we generated a transgenic mouse (Hif1-α(ΔIEC) mice), which was knocked out Hif1-α specifically in IECs, to study the effect of Hif1-α on IEL. IELs were isolated from the small intestine and colon of mice, respectively, and examined by flow cytometry and quantitative real-time PCR. All the cytokines expression was detected by quantitative real-time PCR. The NSAID enteropathy was induced by gavaged with 5 mg/kg indomethacin and the experimental colitis was induced by administration of 2.5% DSS. We found that the number of IELs is increased in Hif1-α (ΔIEC) mice. It is showed that knockout of Hif1-α in IECs led to significant changes in IEL phenotype, including a marked decline in the CD8αα(+) and TCRγδ(+) population. The reduction of CD8αα(+) IELs is accompanied by increased apoptosis, decreased proliferation and weakened migration in Hif1-α(ΔIEC) mice. Moreover, absence of intestinal epithelial Hif1-α markedly changed the population of IELs in NSAID-induced small intestinal injury and increased susceptibility to dextran sulfate sodium-induced colitis. In summary, our results first time demonstrate that IEC-derived Hif1-α is essential for maintaining IELs homeostasis and intestinal microbiota.