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

Abstract

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.

Patient Derived Colonoids as Drug Testing Platforms–Critical Importance of Oxygen Concentration

“…Essential for the colonoid model, we found no differences in cell composition, morphology or cellular apoptosis suggesting that colonoids cultured under a physiological, low oxygen concentration were fully viable. Relevance to IBD is suggested by studies in experimental colitis models ( Sun et al, 2019 ; Colgan et al, 2020 ; Yin et al, 2020 ), and cell lines ( Muenchau et al, 2019 ; Vissenaekens et al, 2019 ), which indicate a protective stabilization of HIF1α, attenuating mucosal inflammation and promoting barrier formation. Moreover, reagents that activate HIF via inhibition of the prolyl hydroxylase enzymes, are suggested to induce hypoxia-mediated resolution in patients with intestinal mucosal inflammatory disease ( Glover and Colgan, 2011 ; Brown et al, 2020 ).…”

The Landscape of Interactions between Hypoxia‐Inducible Factors and Reactive Oxygen Species in the Gastrointestinal Tract

“…Further, there was a significant decrease in the Firmicutes / Bacteroidetes ratio and Lactobacillus abundance, as well as an increased abundance of Akkermansia in intestinal epithelial-specific HIF-1 α knockout mice [ 46 ]. In line with this, it was reported that the abundance of Erysipelotrichales and Lactobacillales increased while the abundance of Bacteroidales and Desulfovibrionale decreased in intestinal epithelial-specific HIF-1 α knockout mice [ 34 ].…”

“…It was also an essential regulator in gastrointestinal immunity. The knockout of HIF-1 α led to a significant decrease of CD8 αα + and TCR γδ + population in intestinal epithelial cells of mice [ 34 ]. Further, activation of HIF-1 α attenuated C .…”

Signaling pathways in intestinal homeostasis and colorectal cancer: KRAS at centre stage

“…Cummins and colleagues also reported the protective role of HIF-1 in in vivo mice model of colonic inflammation by showing that the protection from colitis is associated with reduced apoptosis of colon epithelial cells when HIF-1 is activated [ 55 ]. Moreover, Sun and colleagues showed that IEC-derived HIF-1 contributes to the maintenance of mucosal homeostasis by inducing interleukin (IL-33) expression in IBD [ 56 ], and later the same group showed that IECs-derived HIF-1 is essential for the homeostasis of intestinal intraepithelial lymphocytes and intestinal microbiota [ 57 ]. Altogether these findings suggest that HIF-1 is essential not only for the IECs but also for the maintenance of the colon environmental homeostasis balancing the microbiota and the immune cells.…”

“…The most well-characterized targets are involved in the maintenance of ISCs [50], in metabolic reprogramming [51][52][53], in the regulation of oxygen supply, and in angiogenesis [54]. Different studies have shown that the activation of HIF-1 plays a major role in the maintenance of colon homeostasis [49][50][51][52][53][54][55][56][57]. First, Karhaussen and colleagues demonstrated that epithelial HIF-1 has a protective effect in murine colitis and the loss of HIF-1 results in the loss of barrier function during colitis in vivo in mice [49].…”