Gleeson, L. E. | bioRxiv Science

bioRxiv2025

Immunometabolic Reprogramming of Monocytes in Tuberculosis Infection and Disease

RationaleMonocytes are central to host defence against Mycobacterium tuberculosis (Mtb), yet their functional and metabolic profiles during latent TB infection (TBI) and active TB disease (TBD) remain poorly defined. Immunometabolic dysfunction may underlie ineffective responses in TB, but cell-specific mechanisms are unclear. ObjectivesTo compare the phenotypic, functional, and metabolic profiles of circulating monocytes from individuals with TBI, TBD, and healthy controls (HC), and assess the impact of treatment. MeasurementsPeripheral blood monocytes were profiled using high-dimensional flow cytometry, Luminex cytokine/chemokine assays, and SCENITH, a flow-based metabolic assay. Unstimulated and Mtb-stimulated monocytes from treatment-naive and treated individuals were analysed. Main ResultsMonocytes from TBI and TBD showed distinct phenotypes from HC, marked by elevated CD14 and CD45RA. HLA-DR was reduced in TBI versus HC and further decreased in TBD. TNF receptors were downregulated in TBI but unchanged in TBD. Baseline cytokine and chemokine profiles in TBI and TBD were similar (yet distinct from HC), but Mtb stimulation elicited a stronger cytokine response in TBI. Metabolically, TBI and TBD monocytes exhibited increased glycolysis and reduced mitochondrial dependence versus HC. Treatment partially restored mitochondrial function. Upon Mtb challenge, TBI monocytes had higher glycolytic capacity than TBD. ConclusionsMonocyte metabolic plasticity and cytokine production distinguish latent from active TB and are partially reversible with treatment. Circulating monocyte metabolism reflects TB immune status and may serve as a biomarker or therapeutic target. Reprogrammed glycolytic profiles in TBI contrast with impaired adaptability in TBD, suggesting dysfunctional myeloid activation during disease.

immunology↗

bioRxiv2024

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

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.

immunology↗