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

ABSTRACT: Hif-1? 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-1? 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-1? on intestinal intraepithelial lymphocyte (IEL). Therefore, we generated a transgenic mouse (Hif1-? ?IEC mice), which was knocked out Hif1-? specifically in IECs, to study the effect of Hif1-? 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-? ?IEC mice. It is showed that knockout of Hif1-? in IECs led to significant changes in IEL phenotype, including a marked decline in the CD8??+ and TCR??+ population. The reduction of CD8??+ IELs is accompanied by increased apoptosis, decreased proliferation and weakened migration in Hif1-? ?IEC mice. Moreover, absence of intestinal epithelial Hif1-? 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-? is essential for maintaining IELs homeostasis and intestinal microbiota.

SUBMITTER: Sun L

PROVIDER: S-EPMC6476974 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Sun Lihua L Li Teming T Tang Hanlin H Yu Kun K Ma Yuanhang Y Yu Min M Qiu Yuan Y Xu Pengyuan P Xiao Weidong W Yang Hua H

Frontiers in immunology 20190416

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 <sup><i>ΔIEC</i></sup> mice), which was knocke ...[more]

PMID: 31040849

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Project description:Hypoxia is a notable feature of inflammatory bowel disease and chronic induction of hypoxia-inducible factor (HIF)-1α and HIF-2α (endothelial PAS domain protein 1, EPAS1) play important, but opposing, roles in its pathogenesis. While activation of HIF-1α decreases intestinal inflammation and is beneficial in colitis, activation of HIF-2α exacerbates colitis and increases colon carcinogenesis in animal models, primarily due to the role of epithelial HIF-2α in mounting a potent inflammatory response. Previous work from our laboratory showed that mice overexpressing intestinal epithelial HIF-2α led to massive intestinal inflammation and decreased survival. As oxygen homeostasis and HIFs are critical in embryonic development, it is not clear whether the observed intestinal inflammatory response was secondary to developmental defects. To address this question, the present study used a mouse model to temporally modulate expression of intestinal epithelial HIF-2α to assess its role in mediating inflammatory response. Remarkably, activation of HIF-2α in intestinal epithelial cells in adult mice increased expression of proinflammatory mediators; however, no decrease in survival was observed. Furthermore, in an acute model of colitis, activation of HIF-2α was sufficient to exacerbate colitis. These data confirm our previous finding that epithelial HIF-2α mediates inflammatory response and demonstrates that activation of HIF-2α is sufficient to exacerbate colitis.NEW & NOTEWORTHY Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disease of the intestinal tract. Hypoxia and activation of its downstream transcription factors hypoxia-inducible factor (HIF)-1α and HIF-2α are notable features of IBD. HIF-1α has well-characterized protective roles in IBD; however, the role of HIF-2α has been less studied. Using novel HIF-2α mouse models, we show that activation of HIF-2α in intestinal epithelial cells is sufficient to exacerbate colitis.

Dataset Information

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

Publications

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

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