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While the effects of hypoxia on neutrophil longevity and function have been widely studied, little is known about the consequences of this stimulus on eosinophils.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>We sought to investigate the effects of hypoxia on several key aspects of eosinophil biology, namely secretion, survival, and their sensitivity to glucocorticosteroids (<jats:styled-content style=\"fixed-case\">GCS<\/jats:styled-content>), agents that normally induce eosinophil apoptosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Eosinophils derived from patients with asthma\/atopy or healthy controls were incubated under normoxia and hypoxia, with or without glucocorticoids. Activation was measured by flow cytometry, <jats:styled-content style=\"fixed-case\">ELISA<\/jats:styled-content> of cultured supernatants, and F\u2010actin staining; apoptosis and efferocytosis by morphology and flow cytometry; and <jats:styled-content style=\"fixed-case\">GCS<\/jats:styled-content> efficacy by apoptosis assays and <jats:styled-content style=\"fixed-case\">qPCR<\/jats:styled-content>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Hypoxic incubation (3 <jats:styled-content style=\"fixed-case\">kP<\/jats:styled-content>a) caused (i) stabilization of <jats:styled-content style=\"fixed-case\">HIF<\/jats:styled-content>\u20102\u03b1 and up\u2010regulation of hypoxia\u2010regulated genes including <jats:styled-content style=\"fixed-case\">BNIP<\/jats:styled-content>3 (<jats:styled-content style=\"fixed-case\">BCL<\/jats:styled-content>2\/adenovirus E1B 19\u2010<jats:styled-content style=\"fixed-case\">kD<\/jats:styled-content>a protein\u2010interacting protein 3) and <jats:styled-content style=\"fixed-case\">GLUT<\/jats:styled-content>1 (glucose transporter 1); (ii) secretion of pre\u2010formed <jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20108, and Charcot Leyden crystal (<jats:styled-content style=\"fixed-case\">CLC<\/jats:styled-content>) formation, which was most evident in eosinophils derived from atopic and asthmatic donors; (iii) enhanced F\u2010actin formation; (iv) marked prolongation of eosinophil lifespan (via a <jats:styled-content style=\"fixed-case\">NF<\/jats:styled-content>\u2010\u03baB and Class I <jats:styled-content style=\"fixed-case\">PI<\/jats:styled-content>3\u2010kinase\u2010dependent mechanism); and (v) complete abrogation of the normal pro\u2010apoptotic effect of dexamethasone and fluticasone furoate. This latter effect was evident despite preservation of <jats:styled-content style=\"fixed-case\">GCS<\/jats:styled-content>\u2010mediated gene transactivation under hypoxia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Clinical Relevance<\/jats:title><jats:p>These data indicate that hypoxia promotes an eosinophil pro\u2010inflammatory phenotype by enhancing eosinophil secretory function, delaying constitutive apoptosis, and importantly, antagonizing the normal pro\u2010apoptotic effect of <jats:styled-content style=\"fixed-case\">GCS<\/jats:styled-content>. As eosinophils typically accumulate at sites that are relatively hypoxic, particularly during periods of inflammation, these findings may have important implications to understanding the behaviour of these cells <jats:italic>in vivo<\/jats:italic>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cea.12877","type":"journal-article","created":{"date-parts":[[2016,12,21]],"date-time":"2016-12-21T13:53:55Z","timestamp":1482328435000},"page":"770-784","source":"Crossref","is-referenced-by-count":24,"title":["Hypoxia causes <scp>IL<\/scp>\u20108 secretion, Charcot Leyden crystal formation, and suppression of corticosteroid\u2010induced apoptosis in human eosinophils"],"prefix":"10.1111","volume":"47","author":[{"given":"L. M.","family":"Porter","sequence":"first","affiliation":[{"name":"Department of Medicine University of Cambridge School of Clinical Medicine Addenbrooke's and Papworth Hospitals Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. 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