Chronic IFNα treatment induces leukopoiesis, increased plasma succinate and immune cell metabolic rewiring

Yennemadi, Anjali S.; Jameson, Gráinne; Glass, M.; Pasquale, Carolina De; Keane, Joseph; Bianchi, Massimiliano; Leisching, Gina

doi:10.1016/j.cellimm.2023.104741

Cited by 3 publications

(1 citation statement)

References 17 publications

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“…18,19 A recent study found that type I IFNs, specifically IFNβ, decrease macrophage energy metabolism during mycobacterial infection. 20 Employing our in vivo model of chronic IFNα2a treatment in male Wistar rats, we stimulated bone marrow-derived macrophages (BMDMs) with iH37Rv, 21 replicating the experimental approach described in this paper. Notably, we observed that BMDMs from rats treated with IFNα2a were less effective in upregulating glycolysis in response to iH37Rv compared to BMDMs from rats treated with saline.…”

Section: Discussionmentioning

confidence: 99%

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,

Yennemadi,

Gogan

et al. 2023

Preprint

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In the context of acute settings, the roles of type I interferons (IFNs), notably subtypes IFNα2a, 2b, and β, 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 IFNα and IFNβ. Agilent Seahorse assays demonstrated that IFNβ significantly diminishes the oxygen consumption rate and glycolytic proton extrusion rate in macrophages. Conversely, IFNα2b 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 α2a, α2b, and β 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 IFNα, 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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Section: Discussionmentioning

confidence: 99%

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,

Yennemadi,

Gogan

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

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

Leisching,

Yennemadi,

Gogan

et al. 2024

Eur J Immunol

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The impact of chronic exposure to type I interferons (IFN)‐α2a, 2b, and β on macrophage metabolism, intimately linked to macrophage function, is not well understood. This study assesses the nuanced host responses induced by type I IFN cytokines, offering insights into potential therapeutic approaches in diseases associated with these cytokines. Employing a combination of transcriptional profiling and real‐time functional analysis, we delineated metabolic reprogramming in response to chronic IFN exposure. Our results reveal distinct transcriptional metabolic profiles between macrophages chronically exposed to IFN‐α and IFN‐β. IFN‐β significantly diminishes the oxygen consumption rate and glycolytic proton extrusion rate in macrophages. Conversely, IFN‐α2b decreased parameters of mitochondrial fitness and induced a shift toward 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 IFN‐α2a, α2b, and β on macrophage metabolism but also highlight their potential implications for developing targeted therapeutic strategies.

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The Link Between Dysregulated Immunometabolism and Vascular Damage: Implications for the Development of Atherosclerosis in Systemic Lupus Erythematosus and Other Rheumatic Diseases

Yennemadi,

Jordan,

Diong

et al. 2024

J Rheumatol

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A bimodal pattern of mortality in Systemic Lupus Erythematosus (SLE) exists. Early-stage deaths are predominantly caused by infection, while later-stage deaths are caused mainly by atherosclerotic disease. Further, while SLE-related mortality has reduced considerably in recent years, cardiovascular events remain one of the leading causes of death in people with SLE. Accelerated atherosclerosis in SLE is attributed both to an increase in traditional cardiovascular risk factors and the inflammatory effects of SLE itself. Many of these changes occur within the microenvironment of the vascular-immune interface, the site of atherosclerotic plaque development. Here, an intimate interaction between endothelial cells, vascular smooth muscle cells, and immune cells, dictates physiological versus pathological responses to a chronic type 1 interferon environment. Low-density neutrophils (LDNs) have also been implicated in eliciting vasculature-damaging effects at such lesion sites. These changes are thought to be governed by dysfunctional metabolism of immune cells in this niche due, at least in part, to the chronic induction of type 1 interferons. Understanding of these novel pathophysiological mechanisms and metabolic pathways may unveil potential innovative pharmacological targets and therapeutic opportunities for atherosclerosis, as well as shed light on the development of premature atherosclerosis in SLE patients who develop cardiovascular events.

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Chronic IFNα treatment induces leukopoiesis, increased plasma succinate and immune cell metabolic rewiring

Cited by 3 publications

References 17 publications

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

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

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

The Link Between Dysregulated Immunometabolism and Vascular Damage: Implications for the Development of Atherosclerosis in Systemic Lupus Erythematosus and Other Rheumatic Diseases

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