Local Stabilization of Hypoxia-Inducible Factor-1α Controls Intestinal Inflammation via Enhanced Gut Barrier Function and Immune Regulation

Kim, Young–In; Yi, Eun-Je; Kim, Young-Dae; Lee, A Reum; Chung, Jiwoung; Ha, Hae Chan; Cho, Joong Myung; Kim, Seong-Ryeol; Ko, Hyun‐Jeong; Cheon, Jae Hee; Hong, Yourae; Chang, Shau‐Jin

doi:10.3389/fimmu.2020.609689

Cited by 36 publications

(31 citation statements)

References 65 publications

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“…Hypoxia leading to hypoxia-inducible factor (HIF)-signaling pathway activation is a common feature of inflammatory diseases, including IBD ( Kerber et al, 2020 ). HIF-1 α is protective in IBD models ( Kim et al, 2021 ), and HIF-2 α is essential in maintaining the immune response and regenerative capacity of the intestinal epithelium in IBD ( Ramakrishnan and Shah, 2016 ). At the same time, HIF-2 α but not HIF-1 α constitutive activation leads to IBD development or exacerbation in colitis models ( Xue et al, 2013 ; Solanki et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

HIF-Dependent NFATC1 Activation Upregulates ITGA5 and PLAUR in Intestinal Epithelium in Inflammatory Bowel Disease

et al. 2021

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Intestinal epithelial cells exist in physiological hypoxia, leading to hypoxia-inducible factor (HIF) activation and supporting barrier function and cell metabolism of the intestinal epithelium. In contrast, pathological hypoxia is a common feature of some chronic disorders, including inflammatory bowel disease (IBD). This work was aimed at studying HIF-associated changes in the intestinal epithelium in IBD. In the first step, a list of genes responding to chemical activation of hypoxia was obtained in an in vitro intestinal cell model with RNA sequencing. Cobalt (II) chloride and oxyquinoline treatment of both undifferentiated and differentiated Caco-2 cells activate the HIF-signaling pathway according to gene set enrichment analysis. The core gene set responding to chemical hypoxia stimulation in the intestinal model included 115 upregulated and 69 downregulated genes. Of this set, protein product was detected for 32 genes, and fold changes in proteome and RNA sequencing significantly correlate. Analysis of publicly available RNA sequencing set of the intestinal epithelial cells of patients with IBD confirmed HIF-1 signaling pathway activation in sigmoid colon of patients with ulcerative colitis and terminal ileum of patients with Crohn’s disease. Of the core gene set from the gut hypoxia model, expression activation of ITGA5 and PLAUR genes encoding integrin α5 and urokinase-type plasminogen activator receptor (uPAR) was detected in IBD specimens. The interaction of these molecules can activate cell migration and regenerative processes in the epithelium. Transcription factor analysis with the previously developed miRGTF tool revealed the possible role of HIF1A and NFATC1 in the regulation of ITGA5 and PLAUR gene expression. Detected genes can serve as markers of IBD progression and intestinal hypoxia.

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Section: Introductionmentioning

confidence: 99%

HIF-Dependent NFATC1 Activation Upregulates ITGA5 and PLAUR in Intestinal Epithelium in Inflammatory Bowel Disease

et al. 2021

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“…Studies have also shown that genetic deletion of PHD-1 in murine models of dextran sulfate sodium (DSS) -induced colitis protected against disease (26). Furthermore, various pharmacological compounds that influence the HIF pathway have demonstrated a protective role in murine models of colitis, and in suppression of disease associated inflammation (27)(28)(29)(30). Thus, one possible interpretation of our data is that some of these findings cited above of an anti-inflammatory role for HIF may be due to a HIF-regulated myeloid cell suppression of T cell-induced or -dependent tissue damage.…”

Section: Discussionmentioning

confidence: 99%

Oxygen-Mediated Suppression of CD8+ T Cell Proliferation by Macrophages: Role of Pharmacological Inhibitors of HIF Degradation

et al. 2021

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Myeloid cell interactions with cells of the adaptive immune system are an essential aspect of immunity. A key aspect of that interrelationship is its modulation by the microenvironment. Oxygen is known to influence myelosuppression of T cell activation in part via the Hypoxia inducible (HIF) transcription factors. A number of drugs that act on the HIF pathway are currently in clinical use and it is important to evaluate how they act on immune cell function as part of a better understanding of how they will influence patient outcomes. We show here that increased activation of the HIF pathway, either through deletion of the negative regulator of HIF, the von Hippel-Lindau (VHL) gene, in myeloid cells, or through pharmacological inhibitors of VHL-mediated degradation of HIF, potently suppresses T cell proliferation in myeloid cell/T cell culture. These data demonstrate that both pharmacological and genetic activation of HIF in myeloid cells can suppress adaptive cell immune response.

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“…Hypoxia has also been studied in the context of IBD, and several studies showed that hypoxia inducible factor 1 subunit alpha (HIF-1α) inhibitors improve intestinal barrier function when administered orally [ 129 ] or intraperitoneally [ 130 ]. miR-135a was found to be suppressed in both UC and CD patients [ 86 ].…”

Section: Microrna As a Therapeutic Target In Ibdmentioning

confidence: 99%

Role of MicroRNA in Inflammatory Bowel Disease: Clinical Evidence and the Development of Preclinical Animal Models

Suri

Bubier

Wiles

et al. 2021

Cells

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The dysregulation of microRNA (miRNA) is implicated in cancer, inflammation, cardiovascular disorders, drug resistance, and aging. While most researchers study miRNA’s role as a biomarker, for example, to distinguish between various sub-forms or stages of a given disease of interest, research is also ongoing to utilize these small nucleic acids as therapeutics. An example of a common pleiotropic disease that could benefit from miRNA-based therapeutics is inflammatory bowel disease (IBD), which is characterized by chronic inflammation of the small and large intestines. Due to complex interactions between multiple factors in the etiology of IBD, development of therapies that effectively maintain remission for this disease is a significant challenge. In this review, we discuss the role of dysregulated miRNA expression in the context of clinical ulcerative colitis (UC) and Crohn’s disease (CD)—the two main forms of IBD—and the various preclinical mouse models of IBD utilized to validate the therapeutic potential of targeting these miRNA. Additionally, we highlight advances in the development of genetically engineered animal models that recapitulate clinical miRNA expression and provide powerful preclinical models to assess the diagnostic and therapeutic promise of miRNA in IBD.

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Local Stabilization of Hypoxia-Inducible Factor-1α Controls Intestinal Inflammation via Enhanced Gut Barrier Function and Immune Regulation

Cited by 36 publications

References 65 publications

HIF-Dependent NFATC1 Activation Upregulates ITGA5 and PLAUR in Intestinal Epithelium in Inflammatory Bowel Disease

HIF-Dependent NFATC1 Activation Upregulates ITGA5 and PLAUR in Intestinal Epithelium in Inflammatory Bowel Disease

Oxygen-Mediated Suppression of CD8+ T Cell Proliferation by Macrophages: Role of Pharmacological Inhibitors of HIF Degradation

Role of MicroRNA in Inflammatory Bowel Disease: Clinical Evidence and the Development of Preclinical Animal Models

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