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House dust mite (HDM) triggers asthma by promoting type 2 responses and allergic inflammation via the TLR4 pathway. Although linked to asthma, the role of GSTO1\u20101 in facilitating type 2 responses and\/or HDM\u2010driven allergic inflammation is unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>To determine the role of GSTO1\u20101 in regulating HDM\u2010induced allergic inflammation in a preclinical model of asthma.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Wild\u2010type and GSTO1\u20101\u2010deficient mice were sensitized and aeroallergen challenged with HDM to induce allergic inflammation and subsequently hallmark pathophysiological features characterized.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>By contrast to HDM\u2010challenged WT mice, exposed GSTO1\u20101\u2010deficient mice had increased numbers of eosinophils and macrophages and elevated levels of eotaxin\u20101 and \u20102 in their lungs. M1 macrophage\u2010associated factors, such as IL\u20101\u03b2 and IL\u20106, were decreased in GSTO1\u20101\u2010deficient mice. Conversely, M2 macrophage factors such as Arg\u20101 and Ym1 were up\u2010regulated. HIF\u20101\u03b1 expression was found to be higher in the absence of GSTO1\u20101 and correlated with the up\u2010regulation of M2 macrophage markers. Furthermore, HIF\u20101\u03b1 was shown to bind and activate the eotaxin\u20102 promotor. Hypoxic conditions induced significant increases in the levels of eotaxin\u20101 and \u20102 in GSTO1\u2010deficient BMDMs, providing a potential link between inflammation\u2010induced hypoxia and the regulation of M2 responses in the lung. Collectively, our results suggest that GSTO1\u20101 deficiency promotes M2\u2010type responses and increased levels of nuclear HIF\u20101\u03b1, which regulates eotaxin (s)\u2010induced eosinophilia and increased disease severity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion &amp; Clinical Implication<\/jats:title><jats:p>We propose that GSTO1\u20101 is a novel negative regulator of TLR4\u2010regulated M2 responses acting as an anti\u2010inflammatory pathway. The discovery of a novel HIF\u20101\u03b1\u2010induced eotaxin pathway identifies an unknown connection between hypoxia and the regulation of the severity of allergic inflammation in asthma.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cea.13582","type":"journal-article","created":{"date-parts":[[2020,2,13]],"date-time":"2020-02-13T07:24:44Z","timestamp":1581578684000},"page":"609-624","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["GSTO1\u20101 is an upstream suppressor of M2 macrophage skewing and HIF\u20101\u03b1\u2010induced eosinophilic airway inflammation"],"prefix":"10.1111","volume":"50","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1344-5493","authenticated-orcid":false,"given":"Leon A.","family":"Sokulsky","sequence":"first","affiliation":[{"name":"Faculty of Health and Medicine School of Biomedical Sciences and Pharmacy University of Newcastle Callaghan NSW Australia"},{"name":"Hunter Medical Research 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