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Immunol."],"abstract":"<jats:p>Cutaneous leishmaniasis (CL) contributes significantly to the global burden of neglected tropical diseases, with 12 million people currently infected with <jats:italic>Leishmania<\/jats:italic> parasites. CL encompasses a range of disease manifestations, from self-healing skin lesions to permanent disfigurations. Currently there is no vaccine available, and many patients are refractory to treatment, emphasizing the need for new therapeutic targets. Previous work demonstrated macrophage HIF-\u03b1-mediated lymphangiogenesis is necessary to achieve efficient wound resolution during murine <jats:italic>L. major<\/jats:italic> infection. Here, we investigate the role of macrophage HIF-\u03b1 signaling independent of lymphangiogenesis. We sought to determine the relative contributions of the parasite and the host-mediated inflammation in the lesional microenvironment to myeloid HIF-\u03b1 signaling. Because HIF-\u03b1 activation can be detected in infected and bystander macrophages in leishmanial lesions, we hypothesize it is the host\u2019s inflammatory response and microenvironment, rather than the parasite, that triggers HIF-\u03b1 activation. To address this, macrophages from mice with intact HIF-\u03b1 signaling (LysM<jats:sup>Cre<\/jats:sup>ARNT<jats:sup>f\/+<\/jats:sup>) or mice with deleted HIF-\u03b1 signaling (LysM<jats:sup>Cre<\/jats:sup>ARNT<jats:sup>f\/f<\/jats:sup>) were subjected to RNASequencing after <jats:italic>L. major<\/jats:italic> infection and under pro-inflammatory stimulus. We report that <jats:italic>L. major<\/jats:italic> infection alone is enough to induce some minor HIF-\u03b1-dependent transcriptomic changes, while infection with <jats:italic>L. major<\/jats:italic> in combination with pro-inflammatory stimuli induces numerous transcriptomic changes that are both dependent and independent of HIF-\u03b1 signaling. Additionally, by coupling transcriptomic analysis with several pathway analyses, we found HIF-\u03b1 suppresses pathways involved in protein translation during <jats:italic>L. major<\/jats:italic> infection in a pro-inflammatory environment. Together these findings show <jats:italic>L. major<\/jats:italic> induces a HIF-\u03b1-dependent transcriptomic program, but HIF-\u03b1 only suppresses protein translation in a pro-inflammatory environment. Thus, this work indicates the host inflammatory response, rather than the parasite, largely contributes to myeloid HIF-\u03b1 signaling during <jats:italic>Leishmania<\/jats:italic> infection.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1487311","type":"journal-article","created":{"date-parts":[[2025,3,21]],"date-time":"2025-03-21T17:15:09Z","timestamp":1742577309000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["HIF-\u03b1 signaling regulates the macrophage inflammatory response during Leishmania major infection"],"prefix":"10.3389","volume":"16","author":[{"given":"Lucy G.","family":"Fry","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charity 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