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-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 do not decrease oxidative phosphorylation unlike MDM which shift 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 were 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 are a tractable target for inhalable immunomodulatory therapies for respiratory diseases.
Keywords: Mycobacterium tuberculosis; airway macrophages; cytokines; human; immunology; inflammation; lipopolysaccharide; metabolism; polarization.
Inside the human body, immune cells known as macrophages are constantly looking for microbes, cell debris and other potential threats to engulf and digest. If a macrophage detects a microbe, it activates and releases molecules called cytokines, which induce further immune responses that help to eliminate the invader. The macrophages found in the lungs, known as airway macrophages, defend against pollutants and airborne microbes and are therefore key for maintaining respiratory health. Despite this, previous studies have suggested that airway macrophages are not as good at responding to infections as other types of macrophages. Certain cytokines can cause macrophages to switch how they generate the chemical energy needed to fuel various processes in the cell. However, it remains unclear if it may be possible to develop therapies that boost airway macrophage activity during infection by modifying how they produce chemical energy. To investigate, Cox et al. compared how human airway macrophages and macrophages that originate in the blood alter their production of chemical energy in response to cues from the immune system that indicate an infection is present. The experiments showed that exposure to a specific cytokine known as IFN-γ caused both macrophage types to produce more chemical energy using a metabolic process known as glycolysis. Inhibiting glycolysis induced by IFN-γ had a much bigger effect on the ability of the airway macrophages to produce cytokines than it had on blood macrophages. Furthermore, glycolysis controlled the production of a particular cytokine called TNF in the airway macrophages, but not the blood macrophages. The findings demonstrate that airway macrophages alter how they produce chemical energy during infections in a different way to blood macrophages. Since TNF is a crucial cytokine for defending against respiratory infections, understanding how it is regulated in the lung could help researchers to develop inhalable therapies to boost its production in patients with respiratory infections that are difficult to treat. The specificity of this approach could ultimately limit side effects compared to therapies that act throughout the body.
© 2024, Cox et al.