Pharmacologic inhibition of hypoxia‐inducible factor (HIF)‐hydroxylases ameliorates allergic contact dermatitis

Manresa, Mario C.; Smith, Leila; Casals‐Diaz, Laura; Fagundes, Raphael R.; Brown, Eric J.; Radhakrishnan, P.; Murphy, Stephen J.; Crifò, Bianca; Strowitzki, Moritz J.; Halligan, Doug N.; Bogaard, Ellen H. van den; Niehues, Hanna; Schneider, Martin; Taylor, Cormac T.; Steinhoff, Martin

doi:10.1111/all.13655

Cited by 18 publications

(17 citation statements)

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“…deferoxamine, DFO) (Wang & Semenza, 1993), or molecules which compete for 2-oxoglutarate (Mole et al 2003). Modulation of PHD enzyme activity is beneficial in promoting anti-inflammatory responses by selectively inducing cell death in monocytes (Crifo et al 2019), neutrophils (Manresa et al 2019), and enhancing intestinal epithelial barrier function (Cummins et al 2008), in pro-angiogenic responses via the HIF-dependent upregulation of vascular endothelial growth factor (VEGF), offering protection in ischaemic disease (Milkiewicz et al 2004), as well as helping ameliorate anaemia in patients with kidney disease by stimulating erythropoietin (EPO) production and regulating iron absorption and metabolism (Chen et al 2019b,c).…”

Section: Pharmacological Hydroxylase Inhibition and Glycolysismentioning

confidence: 99%

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Regulation of glycolysis by the hypoxia‐inducible factor (HIF): implications for cellular physiology

Kierans

Taylor

2020

The Journal of Physiology

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Previous appointments include a postdoctoral fellowship at Brigham and Women's Hospital and Harvard Medical School (Boston). Professor Taylor was the recipient of the Nature midcareer mentorship award (2014). The Taylor lab investigates the impact of hypoxia and hypercapnia on cellular pathways and function in the context of inflammation and immunity. Sarah Kierans is a PhD student working in the Taylor laboratory on the pathways regulating glycolysis in hypoxia in tumour cells and immune cells.

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Section: Pharmacological Hydroxylase Inhibition and Glycolysismentioning

confidence: 99%

“…2019), neutrophils (Manresa et al . 2019), and enhancing intestinal epithelial barrier function (Cummins et al . 2008), in pro‐angiogenic responses via the HIF‐dependent upregulation of vascular endothelial growth factor (VEGF), offering protection in ischaemic disease (Milkiewicz et al .…”

Section: Introductionmentioning

confidence: 99%

Regulation of glycolysis by the hypoxia‐inducible factor (HIF): implications for cellular physiology

Kierans

Taylor

2020

The Journal of Physiology

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473

300

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“…Recently, it is reported that PHD inhibition reduced TNF-α-induced production of inflammatory chemokines in keratinocytes and ameliorated allergic contact dermatitis [15]. Therefore, we hypothesized that hypoxia of epidermal tissue control TSLP expression, too.…”

Section: Introductionmentioning

confidence: 95%

Hypoxia inhibits TNF-α-induced TSLP expression in keratinocytes

et al. 2019

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The expression of thymic stromal lymphopoietin (TSLP), a cytokine which greatly contributes to the induction of type I allergy, is upregulated in chronic inflammation such as atopic dermatitis and psoriasis. As hypoxia in the epidermis is important for maintaining skin homeostasis, we examined the regulation of TSLP expression by hypoxic conditions in normal skin epithelial tissues. TNF-α-induced expression of TSLP in human keratinocyte HaCaT and in mouse keratinocyte PAM212 cell lines were inhibited under hypoxic condition (1% O2), although the mRNA expressions of TNF-α, IL-6, IL-8, MCP-1, and VEGF-A were not inhibited. Hypoxia-mimicking conditions, which include NiCl2, CoCl2, and DMOG, an inhibitor of 2-oxoglutarate-dependent enzymes, also selectively inhibited TNF-α-induced TSLP expression. These results suggested that inactivation of prolyl hydroxylase by hypoxia and hypoxia-mimicking conditions is involved in the repression of TNF-α-induced TSLP expression. Interestingly, the inhibition of TSLP production by hypoxic treatment was significantly reversed by treatment with the HIF-2α antagonist but not with the HIF-1α inhibitor. DMOG-induced inhibition of TSLP promoter activity was dependent on the -71 to +185 bp promoter region, suggesting that the binding of HIF-2 to hypoxia response element (HRE) in this region repressed the TSLP expression. These results indicated that hypoxia and hypoxia-mimicking conditions inhibited TSLP expression via HIF-2 and HRE-dependent mechanisms. Therefore, PHD and HIF-2α could be a new strategy for treatment of atopic dermatitis and psoriasis.

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“…As TNF-TNFR2 interaction contributes to the exacerbation of AD, targeting TNF-TNFR2 in AD is a promising therapy [43]. HIF hydroxylases and HIF pathway have been reported in AD, and pharmacologic inhibition of HIF hydroxylases has been suggested to be a novel therapeutic approach in treating allergic contact dermatitis [44]. Although AD is a Th2-dominated disease with overexpression of IL-4, IL-5, and IL-13, the dysregulation of IL-17/Th17 in AD was reported in several studies [45,46].…”

Section: Discussionmentioning

confidence: 99%

The Active Compounds and Therapeutic Mechanisms of Pentaherbs Formula for Oral and Topical Treatment of Atopic Dermatitis Based on Network Pharmacology

Chu

Tsang

et al. 2020

Plants

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To examine the molecular targets and therapeutic mechanism of a clinically proven Chinese medicinal pentaherbs formula (PHF) in atopic dermatitis (AD), we analyzed the active compounds and core targets, performed network and molecular docking analysis, and investigated interacting pathways. Information on compounds in PHF was obtained from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, and target prediction was performed using the Drugbank database. AD-related genes were gathered using the GeneCards and Online Mendelian Inheritance in Man (OMIM) databases. Network analysis was performed by Cytoscape software and protein-protein interaction was analyzed by the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING). The Database for Annotation, Visualization and Integrated Discovery (DAVID) Bioinformatics Resources were applied for the enrichment analysis of the potential biological process and pathways associated with the intersection targets between PHF and AD. Autodock software was used to perform protein compound docking analysis. We identified 43 active compounds in PHF associated with 117 targets, and 57 active compounds associated with 107 targets that form the main pathways linked to oral and topical treatment of AD, respectively. Among them, quercetin, luteolin, and kaempferol are key chemicals targeting the core genes involved in the oral use of PHF against AD, while apigenin, ursolic acid, and rosmarinic acid could be used in topical treatment of PHF against AD. The compound–target–disease network constructed in the current study reveals close interactions between multiple components and multiple targets. Enrichment analysis further supports the biological processes and signaling pathways identified, indicating the involvement of IL-17 and tumor necrosis factor signaling pathways in the action of PHF on AD. Our data demonstrated the main compounds and potential pharmacological mechanisms of oral and topical application of PHF in AD.

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Pharmacologic inhibition of hypoxia‐inducible factor (HIF)‐hydroxylases ameliorates allergic contact dermatitis

Cited by 18 publications

References 64 publications

Regulation of glycolysis by the hypoxia‐inducible factor (HIF): implications for cellular physiology

Regulation of glycolysis by the hypoxia‐inducible factor (HIF): implications for cellular physiology

Hypoxia inhibits TNF-α-induced TSLP expression in keratinocytes

The Active Compounds and Therapeutic Mechanisms of Pentaherbs Formula for Oral and Topical Treatment of Atopic Dermatitis Based on Network Pharmacology

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