Human airway macrophages are metabolically reprogrammed by IFN-[gamma] resulting in glycolysis-dependent functional plasticity

• Published in: eLife 2024-12, Vol.13
• Main Authors: Cox, Donal J, Connolly, Sarah A, Ó Maoldomhnaigh, Cilian, Brugman, Aenea AI, Sandby Thomas, Olivia, Duffin, Emily, Gogan, Karl M, Ó Gallchobhair, Oisin, Murphy, Dearbhla M, O'Rourke, Sinead A, O'Connell, Finbarr, Nadarajan, Parthiban, Phelan, James J, Gleeson, Laura E, Basdeo, Sharee A, Keane, Joseph
• Format: Article
• Language: English
• Subjects: Analysis; Glucose metabolism; Health aspects; Macrophages; Physiological aspects
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.98449

Airway macrophages (AM) are the predominant immune cell in the lung and play a crucial role in preventing infection, making them a target for host directed therapy. 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-[gamma] 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-[gamma] or upon stimulation. IFN-[gamma] 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 'Warburg'-like metabolism. IFN-[gamma] priming promoted cytokine secretion in AM. Blocking glycolysis with 2-deoxyglucose significantly reduced IFN-[gamma] driven cytokine production in AM, indicating that IFN-[gamma] induces functional plasticity in human AM, which is mechanistically mediated by glycolysis. Directly comparing responses between macrophages, AM were more responsive to IFN-[gamma] 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-[gamma] upregulated HLA-DR and CD40 on AM independently of glycolysis. These data indicate that human AM are functionally plastic and respond to IFN-[gamma] in a manner distinct from MDM. These data provide evidence that human AM are a tractable target for inhalable immunomodulatory therapies for respiratory diseases.