Mario C Manresa1,2,3, Leila Smith1, Laura Casals-Diaz1, Raphael R Fagundes2, Eric Brown2, Praveen Radhakrishnan4, Stephen J Murphy2, Bianca Crifo2, Moritz J Strowitzki2, Doug N Halligan2, Ellen H van den Bogaard5, Hanna Niehues5, Martin Schneider4, Cormac T Taylor1,2,6, Martin Steinhoff1,7. 1. UCD Charles, Institute of Dermatology School of Medicine and Medical Science, University College Dublin, Belfield, Dublin, Ireland. 2. Conway Institute of Biomedical and Biomolecular Research, School of Medicine and Medical Science, University College Dublin, Belfield, Dublin, Ireland. 3. Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. 4. Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. 5. Department of Dermatology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands. 6. Systems Biology Ireland, School of Medicine and Medical Science, University College Dublin, Belfield, Dublin, Ireland. 7. Department of Dermatology & Venereology, Translational Research Institute, Hamad Medical Corporation, Weill Cornell University-Qatar and Qatar University, Doha, Qatar.
Abstract
BACKGROUND: When an immune cell migrates from the bloodstream to a site of chronic inflammation, it experiences a profound decrease in microenvironmental oxygen levels leading to a state of cellular hypoxia. The hypoxia-inducible factor-1α (HIF-1α) promotes an adaptive transcriptional response to hypoxia and as such is a major regulator of immune cell survival and function. HIF hydroxylases are the family of oxygen-sensing enzymes primarily responsible for conferring oxygen dependence upon the HIF pathway. METHODS: Using a mouse model of allergic contact dermatitis (ACD), we tested the effects of treatment with the pharmacologic hydroxylase inhibitor DMOG, which mimics hypoxia, on disease development. RESULTS: Re-exposure of sensitized mice to 2,4-dinitrofluorobenzene (DNFB) elicited inflammation, edema, chemokine synthesis (including CXCL1 and CCL5) and the recruitment of neutrophils and eosinophils. Intraperitoneal or topical application of the pharmacologic hydroxylase inhibitors dymethyloxalylglycine (DMOG) or JNJ1935 attenuated this inflammatory response. Reduced inflammation was associated with diminished recruitment of neutrophils and eosinophils but not lymphocytes. Finally, hydroxylase inhibition reduced cytokine-induced chemokine production in cultured primary keratinocytes through attenuation of the JNK pathway. CONCLUSION: These data demonstrate that hydroxylase inhibition attenuates the recruitment of neutrophils to inflamed skin through reduction of chemokine production and increased neutrophilic apoptosis. Thus, pharmacologic inhibition of HIF hydroxylases may be an effective new therapeutic approach in allergic skin inflammation.
BACKGROUND: When an immune cell migrates from the bloodstream to a site of chronic inflammation, it experiences a profound decrease in microenvironmental oxygen levels leading to a state of cellular hypoxia. The hypoxia-inducible factor-1α (HIF-1α) promotes an adaptive transcriptional response to hypoxia and as such is a major regulator of immune cell survival and function. HIF hydroxylases are the family of oxygen-sensing enzymes primarily responsible for conferring oxygen dependence upon the HIF pathway. METHODS: Using a mouse model of allergic contact dermatitis (ACD), we tested the effects of treatment with the pharmacologic hydroxylase inhibitor DMOG, which mimics hypoxia, on disease development. RESULTS: Re-exposure of sensitized mice to 2,4-dinitrofluorobenzene (DNFB) elicited inflammation, edema, chemokine synthesis (including CXCL1 and CCL5) and the recruitment of neutrophils and eosinophils. Intraperitoneal or topical application of the pharmacologic hydroxylase inhibitors dymethyloxalylglycine (DMOG) or JNJ1935 attenuated this inflammatory response. Reduced inflammation was associated with diminished recruitment of neutrophils and eosinophils but not lymphocytes. Finally, hydroxylase inhibition reduced cytokine-induced chemokine production in cultured primary keratinocytes through attenuation of the JNK pathway. CONCLUSION: These data demonstrate that hydroxylase inhibition attenuates the recruitment of neutrophils to inflamed skin through reduction of chemokine production and increased neutrophilic apoptosis. Thus, pharmacologic inhibition of HIF hydroxylases may be an effective new therapeutic approach in allergic skin inflammation.
Authors: Moritz J Strowitzki; Gwendolyn Kimmer; Julian Wehrmann; Alina S Ritter; Praveen Radhakrishnan; Vanessa M Opitz; Christopher Tuffs; Marvin Biller; Julia Kugler; Ulrich Keppler; Jonathan M Harnoss; Johannes Klose; Thomas Schmidt; Alfonso Blanco; Cormac T Taylor; Martin Schneider Journal: JCI Insight Date: 2021-03-30
Authors: Jonathan C Strefford; Stephen M Thirdborough; Stephen A Beers; Mark S Cragg; Khiyam Hussain; Rena Liu; Rosanna C G Smith; Kri T J Müller; Mohammadmersad Ghorbani; Sofia Macari; Kirstie L S Cleary; Robert J Oldham; Russell B Foxall; Sonya James; Steven G Booth; Tom Murray; Lekh N Dahal; Chantal E Hargreaves; Robert S Kemp; Jemma Longley; James Douglas; Hannah Markham; Serena J Chee; Richard J Stopforth; Ali Roghanian; Matthew J Carter; Christian H Ottensmeier; Bjorn Frendéus; Ramsey I Cutress; Ruth R French; Martin J Glennie Journal: J Exp Clin Cancer Res Date: 2022-04-07