Interferon α and β induce differential transcriptional and functional metabolic phenotypes in human monocyte-derived macrophages and blunt glycolysis in response to antigenic stimuli.

Leisching, G.; Yennemadi, A.; Gogan, K.; Keane, J.

doi:10.1101/2023.12.16.571975

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bioRxiv · 10.1101/2023.12.16.571975

Interferon α and β induce differential transcriptional and functional metabolic phenotypes in human monocyte-derived macrophages and blunt glycolysis in response to antigenic stimuli.

Leisching, G.·Yennemadi, A.·Gogan, K.·Keane, J.

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Abstract

In the context of acute settings, the roles of type I interferons (IFNs), notably subtypes IFN2a, 2b, and {beta}, in modulating macrophage metabolism and contributing to host defense against viral and bacterial pathogens are well-established. However, the impact of chronic exposure to type I IFNs on macrophage metabolism, intimately linked to macrophage function, remains less understood. This study aimed to unravel the nuanced host responses induced by type I IFN cytokines, offering insights for potential therapeutic approaches in diseases associated with these cytokines.Employing a combination of transcriptional profiling and real-time functional analysis, we delineated the temporal evolution of metabolic reprogramming in response to chronic interferon exposure. Our results reveal distinct transcriptional metabolic profiles between macrophages chronically exposed to IFN and IFN{beta}. Agilent Seahorse assays demonstrated that IFN{beta} significantly diminishes the oxygen consumption rate and glycolytic proton extrusion rate in macrophages. Conversely, IFN2b decreased parameters of mitochondrial fitness and induced a shift towards glutamine oxidation.Assessing the ability of macrophages to induce glycolysis in response to antigenic stimuli (LPS and iH37Rv), we found that chronic exposure to all IFN subtypes limited glycolytic induction. This study addresses a critical oversight in the literature, where individual roles of IFN subtypes are frequently amalgamated and lack distinction. These findings not only provide novel insights into the divergent effects of interferon 2a, 2b, and {beta} on macrophage metabolism but also highlight their potential implications for developing targeted therapeutic strategies. This is particularly relevant in autoimmune disorders where type I IFNs, particularly IFN, play a central role. The observed metabolic quiescence induced by chronic IFN exposure underscores its significance in macrophage functionality and its potential contribution to the pathophysiology of autoimmune disorders and susceptibility to infection.

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Leisching, G., Yennemadi, A., Gogan, K., Keane, J.. 2023-12-16. Interferon α and β induce differential transcriptional and functional metabolic phenotypes in human monocyte-derived macrophages and blunt glycolysis in response to antigenic stimuli.. https://doi.org/10.1101/2023.12.16.571975

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