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Macrophage effector functions are associated with cellular metabolism. A knowledge gap remains in understanding metabolic reprogramming and functional plasticity of distinct human macrophage subpopulations, especially in lung resident AM. We examined tissue-resident AM and monocyte-derived macrophages (MDM; as a model of blood derived macrophages) in their resting state and after priming with IFN-\u03b3 or IL-4 to model the Th1\/Th2 axis in the lung. Human macrophages, regardless of origin, had a strong induction of glycolysis in response to IFN-\u03b3 or upon stimulation. IFN-\u03b3 significantly enhanced cellular energetics in both AM and MDM by upregulating both glycolysis and oxidative phosphorylation. Upon stimulation, AM do not decrease oxidative phosphorylation unlike MDM which shift to \u2018Warburg\u2019-like metabolism. IFN-\u03b3 priming promoted cytokine secretion in AM. Blocking glycolysis with 2-deoxyglucose significantly reduced IFN-\u03b3 driven cytokine production in AM, indicating that IFN-\u03b3 induces functional plasticity in human AM, which is mechanistically mediated by glycolysis. Directly comparing responses between macrophages, AM were more responsive to IFN-\u03b3 priming and dependent on glycolysis for cytokine secretion than MDM. Interestingly, TNF production was under the control of glycolysis in AM and not in MDM. MDM exhibited glycolysis-dependent upregulation of HLA-DR and CD40, whereas IFN-\u03b3 upregulated HLA-DR and CD40 on AM independently of glycolysis. These data indicate that human AM are functionally plastic and respond to IFN-\u03b3 in a manner distinct from MDM. These data provide evidence that human AM are a tractable target for inhalable immunomodulatory therapies for respiratory diseases.<\/jats:p>","DOI":"10.7554\/elife.98449","type":"journal-article","created":{"date-parts":[[2024,6,20]],"date-time":"2024-06-20T12:25:48Z","timestamp":1718886348000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.98449","source":"Crossref","is-referenced-by-count":15,"title":["Human airway macrophages are metabolically reprogrammed by IFN-\u03b3 resulting in glycolysis-dependent functional plasticity"],"prefix":"10.7554","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8523-3836","authenticated-orcid":true,"given":"Donal J","family":"Cox","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02tyrky19","id-type":"ROR","asserted-by":"publisher"}],"name":"Trinity Translational Medicine Institute, St James\u2019s Hospital, Trinity College Dublin, The University of Dublin","place":["Dublin, 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