Immunometabolism: A Therapeutic Target in Cancer and Inflammatory Diseases?

Dear Colleagues,

We have only just begun to realize the relevance of metabolic changes for the immunological functions of macrophages or T cells in physiological and pathophysiological conditions, such as cancer and inflammatory diseases. Interest in the field of immunometabolism, which we define as the interplay between immunological and metabolic processes, is motivated by the realization that a dysregulated metabolism in immune cells is an essential element in the progression of the disease. Manipulating the metabolism of these cells might thus offer new avenues in cancer and inflammatory disease therapy.

The aim of this Special issue is to provide a platform to report and discuss the most recent studies on the immunometabolism of macrophages or T cells not only in one, but in various pathological setups and its relevance to disease progression and/or resistance to therapy. We expect works reporting on the response of macrophages and T cells—in terms of metabolic reprogramming—in various tissues (e.g., brain, bowel, liver) and pathologies (e.g., cancer, autoimmune disease, hepatitis). We therefore anticipate that this Special issue will boost interest in this exciting field by gathering the knowledge that we need for future translational studies.

The scope of the issue encompasses the following areas:
- Metabolic reprogramming (energy, lipid metabolism, amino-acid metabolism, etc.) in macrophages (including brain resident microglia) and T cells in various inflamed tissues and conditions, including cancer;
- Epigenetics of immunometabolism;
- miRNA in immunometabolism of macrophages and T cells;
- Systems biology approaches of immunometabolism, modeling;
- Pathological conditions: cancer, asthma, autoimmune diseases, inflammatory bowel disease, coeliac disease, glomerulonephritis, hepatitis, Lupus, etc.

Dr. Anne Régnier-Vigouroux
Guest Editor

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Macrophages

Microglia

T cells

Immunometabolism

Metabolic reprogramming

Inflammation

Epigenetics

miRNA

Cancer

Inflammatory diseases

Multiomics approaches

Systems biology

Modeling

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Open AccessArticle

Oxidative Stress Differentially Influences the Survival and Metabolism of Cells in the Melanoma Microenvironment

by Emily R. Trzeciak, Niklas Zimmer, Isabelle Gehringer, Lara Stein, Barbara Graefen, Jonathan Schupp, Achim Stephan, Stephan Rietz, Michael Prantner and Andrea Tuettenberg

Cells 2022, 11(6), 930; https://doi.org/10.3390/cells11060930 - 8 Mar 2022

Cited by 8 | Viewed by 3181

Abstract

The cellular composition of the tumor microenvironment, including tumor, immune, stromal, and endothelial cells, significantly influences responses to cancer therapies. In this study, we analyzed the impact of oxidative stress, induced by cold atmospheric plasma (CAP), on tumor cells, T cells, and macrophages, [...] Read more.

The cellular composition of the tumor microenvironment, including tumor, immune, stromal, and endothelial cells, significantly influences responses to cancer therapies. In this study, we analyzed the impact of oxidative stress, induced by cold atmospheric plasma (CAP), on tumor cells, T cells, and macrophages, which comprise part of the melanoma microenvironment. To accomplish this, cells were grown in different in vitro cell culture models and were treated with varying amounts of CAP. Subsequent alterations in viability, proliferation, and phenotype were analyzed via flow cytometry and metabolic alterations by Seahorse Cell Mito Stress Tests. It was found that cells generally exhibited reduced viability and proliferation, stemming from CAP induced G2/M cell cycle arrest and subsequent apoptosis, as well as increased mitochondrial stress following CAP treatment. Overall, sensitivity to CAP treatment was found to be cell type dependent with T cells being the most affected. Interestingly, CAP influenced the polarization of M0 macrophages to a “M0/M2-like” phenotype, and M1 macrophages were found to display a heightened sensitivity to CAP induced mitochondrial stress. CAP also inhibited the growth and killed melanoma cells in 2D and 3D in vitro cell culture models in a dose-dependent manner. Improving our understanding of oxidative stress, mechanisms to manipulate it, and its implications for the tumor microenvironment may help in the discovery of new therapeutic targets. Full article

(This article belongs to the Special Issue Immunometabolism: A Therapeutic Target in Cancer and Inflammatory Diseases?)

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Open AccessArticle

ACLY Nuclear Translocation in Human Macrophages Drives Proinflammatory Gene Expression by NF-κB Acetylation

by Anna Santarsiero, Paolo Convertini, Simona Todisco, Ciro L. Pierri, Anna De Grassi, Niamh C. Williams, Dominga Iacobazzi, Giulio De Stefano, Luke A. J. O’Neill and Vittoria Infantino

Cells 2021, 10(11), 2962; https://doi.org/10.3390/cells10112962 - 30 Oct 2021

Cited by 25 | Viewed by 4826

Abstract

Macrophage stimulation by pathogen-associated molecular patterns (PAMPs) like lipopolysaccharide (LPS) or lipoteichoic acid (LTA) drives a proinflammatory phenotype and induces a metabolic reprogramming to sustain the cell’s function. Nevertheless, the relationship between metabolic shifts and gene expression remains poorly explored. In this context, [...] Read more.

Macrophage stimulation by pathogen-associated molecular patterns (PAMPs) like lipopolysaccharide (LPS) or lipoteichoic acid (LTA) drives a proinflammatory phenotype and induces a metabolic reprogramming to sustain the cell’s function. Nevertheless, the relationship between metabolic shifts and gene expression remains poorly explored. In this context, the metabolic enzyme ATP citrate lyase (ACLY), the producer of citrate-derived acetyl-coenzyme A (CoA), plays a critical role in supporting a proinflammatory response. Through immunocytochemistry and cytosol–nucleus fractionation, we found a short-term ACLY nuclear translocation. Protein immunoprecipitation unveiled the role of nuclear ACLY in NF-κB acetylation and in turn its full activation in human PBMC-derived macrophages. Notably, sepsis in the early hyperinflammatory phase triggers ACLY-mediated NF-κB acetylation. The ACLY/NF-κB axis increases the expression levels of proinflammatory genes, including SLC25A1—which encodes the mitochondrial citrate carrier—and ACLY, thus promoting the existence of a proinflammatory loop involving SLC25A1 and ACLY genes. Full article

(This article belongs to the Special Issue Immunometabolism: A Therapeutic Target in Cancer and Inflammatory Diseases?)

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Open AccessReview

Polyamine Immunometabolism: Central Regulators of Inflammation, Cancer and Autoimmunity

by Tzu-yi Chia, Andrew Zolp and Jason Miska

Cells 2022, 11(5), 896; https://doi.org/10.3390/cells11050896 - 5 Mar 2022

Cited by 23 | Viewed by 4698

Abstract

Polyamines are ubiquitous, amine-rich molecules with diverse processes in biology. Recent work has highlighted that polyamines exert profound roles on the mammalian immune system, particularly inflammation and cancer. The mechanisms by which they control immunity are still being described. In the context of [...] Read more.

Polyamines are ubiquitous, amine-rich molecules with diverse processes in biology. Recent work has highlighted that polyamines exert profound roles on the mammalian immune system, particularly inflammation and cancer. The mechanisms by which they control immunity are still being described. In the context of inflammation and autoimmunity, polyamine levels inversely correlate to autoimmune phenotypes, with lower polyamine levels associated with higher inflammatory responses. Conversely, in the context of cancer, polyamines and polyamine biosynthetic genes positively correlate with the severity of malignancy. Blockade of polyamine metabolism in cancer results in reduced tumor growth, and the effects appear to be mediated by an increase in T-cell infiltration and a pro-inflammatory phenotype of macrophages. These studies suggest that polyamine depletion leads to inflammation and that polyamine enrichment potentiates myeloid cell immune suppression. Indeed, combinatorial treatment with polyamine blockade and immunotherapy has shown efficacy in pre-clinical models of cancer. Considering the efficacy of immunotherapies is linked to autoimmune sequelae in humans, termed immune-adverse related events (iAREs), this suggests that polyamine levels may govern the inflammatory response to immunotherapies. This review proposes that polyamine metabolism acts to balance autoimmune inflammation and anti-tumor immunity and that polyamine levels can be used to monitor immune responses and responsiveness to immunotherapy. Full article

(This article belongs to the Special Issue Immunometabolism: A Therapeutic Target in Cancer and Inflammatory Diseases?)

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26 pages, 1905 KiB  

Open AccessReview

Multistability in Macrophage Activation Pathways and Metabolic Implications

by Carsten Geiß, Elvira Salas, Jose Guevara-Coto, Anne Régnier-Vigouroux and Rodrigo A. Mora-Rodríguez

Cells 2022, 11(3), 404; https://doi.org/10.3390/cells11030404 - 25 Jan 2022

Cited by 23 | Viewed by 6158

Abstract

Macrophages are innate immune cells with a dynamic range of reversible activation states including the classical pro-inflammatory (M1) and alternative anti-inflammatory (M2) states. Deciphering how macrophages regulate their transition from one state to the other is key for a deeper understanding of inflammatory [...] Read more.

Macrophages are innate immune cells with a dynamic range of reversible activation states including the classical pro-inflammatory (M1) and alternative anti-inflammatory (M2) states. Deciphering how macrophages regulate their transition from one state to the other is key for a deeper understanding of inflammatory diseases and relevant therapies. Common regulatory motifs reported for macrophage transitions, such as positive or double-negative feedback loops, exhibit a switchlike behavior, suggesting the bistability of the system. In this review, we explore the evidence for multistability (including bistability) in macrophage activation pathways at four molecular levels. First, a decision-making module in signal transduction includes mutual inhibitory interactions between M1 (STAT1, NF-KB/p50-p65) and M2 (STAT3, NF-KB/p50-p50) signaling pathways. Second, a switchlike behavior at the gene expression level includes complex network motifs of transcription factors and miRNAs. Third, these changes impact metabolic gene expression, leading to switches in energy production, NADPH and ROS production, TCA cycle functionality, biosynthesis, and nitrogen metabolism. Fourth, metabolic changes are monitored by metabolic sensors coupled to AMPK and mTOR activity to provide stability by maintaining signals promoting M1 or M2 activation. In conclusion, we identify bistability hubs as promising therapeutic targets for reverting or blocking macrophage transitions through modulation of the metabolic environment. Full article

(This article belongs to the Special Issue Immunometabolism: A Therapeutic Target in Cancer and Inflammatory Diseases?)

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