Interferon Gamma Induces Reversible Metabolic Reprogramming of M1 Macrophages to Sustain Cell Viability and Pro-Inflammatory Activity

Abstract

Classical activation of M1 macrophages with lipopolysaccharide (LPS) is associated with a metabolic switch from oxidative phosphorylation to glycolysis. However, the generalizability of such metabolic remodeling to other modes of M1 macrophage stimulation, e.g. type II interferons (IFNs) such as IFNγ, has remained unknown as has the functional significance of aerobic glycolysis during macrophage activation. Here we demonstrate that IFNγ induces a rapid activation of aerobic glycolysis followed by a reduction in oxidative phosphorylation in M1 macrophages. Elevated glycolytic flux sustains cell viability and inflammatory activity, while limiting reliance on mitochondrial oxidative metabolism. Adenosine triphosphate (ATP) distributed by aerobic glycolysis is critical for sustaining IFN-γ triggered JAK (Janus tyrosine kinase)-STAT-1 (Signal Transducer and Activator of Transcription 1) signaling with phosphorylation of the transcription factor STAT-1 as its signature trait. Inhibition of aerobic glycolysis not only blocks the M1 phenotype and pro-inflammatory cytokine/chemokine production in murine macrophages and also human monocytes/macrophages. These findings extend on the potential functional role of immuno-metabolism from LPS- to IFNγ-linked diseases such as atherosclerosis and autoimmune disease.

Highlights

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  Interferon gamma (IFNγ) induces a rapid switch to aerobic glycolysis in M1 macrophages sustaining two signaling pathways.

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  Repurposing of the mitochondria, including reactive oxygen species production, allows for HIF-1α and IL-1β production.

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  ATP production by glycolysis allows for JAK activity, STAT-1 phosphorylation, iNOS and thereby nitric oxide production.

Inflammatory cells like macrophages, upon activation, switch their energy metabolism from the mitochondria to the processing of glucose. This switch feeds into the inflammatory action of macrophages and links it to the glucose concentration in the cell environment. Accordingly, under conditions of high glucose concentrations, as seen in patients with diabetes, a higher level of inflammatory activity might be seen. Performing these studies with the macrophage activator interferon gamma that plays a role in the development of narrowing of arteries (atherosclerosis) furthers the potential link of these findings to the more diffuse and aggressive nature of atherosclerosis in diabetic patients.