Human airway macrophages are metabolically reprogrammed by IFN-γ resulting in glycolysis-dependent functional plasticity

Airway macrophages (AM) are the predominant immune cells 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-γ 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-γ or upon stimulation. IFN-γ significantly enhanced cellular
energetics in both AM and MDM by upregulating both glycolysis and
oxidative phosphorylation. Upon stimulation, AM does not decrease
oxidative phosphorylation, unlike MDM which shifts to “Warburg”-like
metabolism. IFN-γ priming promoted cytokine secretion in AM. Blocking
glycolysis with 2-deoxyglucose significantly reduced IFN-γ driven cytokine
production in AM, indicating that IFN-γ induces functional plasticity in
human AM, which is mechanistically mediated by glycolysis. Directly
comparing responses between macrophages, AM was more responsive to IFN-γ
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-γ upregulated HLA-DR and CD40 on AM independently of
glycolysis. These data indicate that human AM are functionally plastic and
respond to IFN-γ in a manner distinct from MDM. These data provide
evidence that human AM is a tractable target for inhalable
immunomodulatory therapies for respiratory diseases.