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

• DOI: 10.1111/all.13655
• Publication Date: 2018-11-05T11:52:13Z
• Authors: Mario C. Manresa; Leila Smith; Laura Casals‐Diaz; Raphael R. Fagundes; Eric Brown; Praveen Radhakris...; Stephen J. Murphy; Bianca Crifo; Moritz J. Strowitzki; Doug N. Halligan; Ellen H. van den ...; Hanna Niehues; Martin Schneider; Cormac T. Taylor; Martin Steinhoff
• Keywords: Hypoxia; Hypoxia-Inducible Factors

Abstract Background When an immune cell migrates from the bloodstream to a site of chronic inflammation, it experiences profound decrease in microenvironmental oxygen levels leading state cellular hypoxia. The hypoxia‐inducible factor‐1α ( HIF ‐1α) promotes adaptive transcriptional response hypoxia and as such is major regulator survival function. hydroxylases are family oxygen‐sensing enzymes primarily responsible for conferring dependence upon pathway. Methods Using mouse model allergic contact dermatitis ACD ), we tested effects treatment with pharmacologic hydroxylase inhibitor DMOG , which mimics hypoxia, on disease development. Results Re‐exposure sensitized mice 2,4‐dinitrofluorobenzene DNFB ) elicited edema, chemokine synthesis (including CXCL 1 CCL 5) recruitment neutrophils eosinophils. Intraperitoneal or topical application inhibitors dymethyloxalylglycine JNJ 1935 attenuated this inflammatory response. Reduced inflammation was associated diminished eosinophils but not lymphocytes. Finally, inhibition reduced cytokine‐induced production cultured primary keratinocytes through attenuation JNK Conclusion These data demonstrate that attenuates inflamed skin reduction increased neutrophilic apoptosis. Thus, may be effective new therapeutic approach inflammation.