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Metabolites
Special Issues
Regulation of Immunity and Inflammation by Immunometabolites and Metabolic Enzymes
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Regulation of Immunity and Inflammation by Immunometabolites and Metabolic Enzymes

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Cell Metabolism".

Deadline for manuscript submissions: closed (31 August 2020) | Viewed by 69061

Special Issue Editors

Dr. Stefano Angiari

E-Mail Website
Guest Editor
School of Biochemistry and Immunology, Trinity Biomedical Sciences, Institute, Trinity College Dublin, 152–160 Pearse Street, Dublin D02 R590, Ireland
Interests: immunometabolism; inflammation; autoimmunity; T cell biology
Dr. Jan Van den Bossche

E-Mail Website
Guest Editor
Department of Molecular Cell Biology and Immunology, Amsterdam UMC, 1081 HZ Amsterdam, The Netherlands
Interests: immunometabolism; innate immunity; macrophage heterogeneity and plasticity; immunometabolites
Special Issues, Collections and Topics in MDPI journals
Dr. Stanley Huang

E-Mail Website
Guest Editor
CASE School of Medicine, 2103 Cornell Road, Cleveland, OH 44106, USA
Interests: innate immunity; macrophages; innate lymphoid cells; immunometabolism
Special Issues, Collections and Topics in MDPI journals
Prof. Luke O'Neill

E-Mail Website
Guest Editor
School of Biochemistry and Immunology, Trinity College Dublin, Ireland
Interests: immunometabolism; inflammation; innate immunity; inflammasomes; signalling in immune cells

Special Issue Information

Dear Colleagues,

Immunology and metabolism have long been viewed as two very distinct fields with minimal or no overlap. However, over the past decade, a fast-growing number of high-impact papers highlighted the intricate link between immune cell metabolism and function. The activation and effector functions of adaptive and innate immune cells are indeed governed by the engagement and modulation of specific intracellular metabolic pathways. Systemic metabolic cues and dysfunctions can also influence how immune cells work, supporting the concept that metabolism and inflammation are tightly connected. For example, metabolites are much more than intermediate or end products of metabolism. We now know that “immunometabolites” like succinate, itaconate, acetyl-CoA, and 2-hydroxyglutarate serve as signal transducers that regulate immune cell function and disease outcome. Moreover, metabolic enzymes such as glyceraldehyde-3-phospahte dehydrogenase (GAPDH) and pyruvate kinase (PK) do much more than converting one metabolite into another.

The scope of this Special Issue will be to update our current knowledge on how metabolites and metabolic enzymes can modulate immunity and inflammation. We welcome high-quality original research articles, as well as reviews and perspectives, that provide new mechanistic insight into the metabolic regulation of immune cells (macrophages, dendritic cells, monocytes, granulocytes, T cells, NK cells, B cells, etc.), and how this affects health and disease. Manuscripts describing new methods developed to investigate metabolite-mediated signalling pathways and the non-canonical role of metabolic enzymes in inflammation are also welcome.

Dr. Stefano Angiari
Dr. Jan Van den Bossche
Dr. Stanley Huang
Prof. Luke O'Neill
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Metabolites is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • immunometabolism
  • immunometabolites
  • metabolic reprogramming
  • metabolism
  • immune cell heterogeneity and plasticity
  • signalling
  • inflammation
  • immunomodulation

Published Papers (11 papers)

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Research

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18 pages, 6820 KiB  
Article
Divergent Impact of Glucose Availability on Human Virus-Specific and Generically Activated CD8 T Cells
by Jenifer Sanchez, Ian Jackson, Katie R. Flaherty, Tamara Muliaditan and Anna Schurich
Metabolites 2020, 10(11), 461; https://doi.org/10.3390/metabo10110461 - 13 Nov 2020
Cited by 4 | Viewed by 2804
Abstract
Upon activation T cells engage glucose metabolism to fuel the costly effector functions needed for a robust immune response. Consequently, the availability of glucose can impact on T cell function. The glucose concentrations used in conventional culture media and common metabolic assays are [...] Read more.
Upon activation T cells engage glucose metabolism to fuel the costly effector functions needed for a robust immune response. Consequently, the availability of glucose can impact on T cell function. The glucose concentrations used in conventional culture media and common metabolic assays are often artificially high, representing hyperglycaemic levels rarely present in vivo. We show here that reducing glucose concentration to physiological levels in culture differentially impacted on virus-specific compared to generically activated human CD8 T cell responses. In virus-specific T cells, limiting glucose availability significantly reduced the frequency of effector-cytokine producing T cells, but promoted the upregulation of CD69 and CD103 associated with an increased capacity for tissue retention. In contrast the functionality of generically activated T cells was largely unaffected and these showed reduced differentiation towards a residency phenotype. Furthermore, T cells being cultured at physiological glucose concentrations were more susceptible to viral infection. This setting resulted in significantly improved lentiviral transduction rates of primary cells. Our data suggest that CD8 T cells are exquisitely adapted to their niche and provide a reminder of the need to better mimic physiological conditions to study the complex nature of the human CD8 T cell immune response. Full article
(This article belongs to the Special Issue Regulation of Immunity and Inflammation by Immunometabolites and Metabolic Enzymes)
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14 pages, 2009 KiB  
Article
Succinate Is an Inflammation-Induced Immunoregulatory Metabolite in Macrophages
by Karl J. Harber, Kyra E. de Goede, Sanne G. S. Verberk, Elisa Meinster, Helga E. de Vries, Michel van Weeghel, Menno P. J. de Winther and Jan Van den Bossche
Metabolites 2020, 10(9), 372; https://doi.org/10.3390/metabo10090372 - 15 Sep 2020
Cited by 60 | Viewed by 6096
Abstract
Immunometabolism revealed the crucial role of cellular metabolism in controlling immune cell phenotype and functions. Macrophages, key immune cells that support progression of numerous inflammatory diseases, have been well described as undergoing vast metabolic rewiring upon activation. The immunometabolite succinate particularly gained a [...] Read more.
Immunometabolism revealed the crucial role of cellular metabolism in controlling immune cell phenotype and functions. Macrophages, key immune cells that support progression of numerous inflammatory diseases, have been well described as undergoing vast metabolic rewiring upon activation. The immunometabolite succinate particularly gained a lot of attention and emerged as a crucial regulator of macrophage responses and inflammation. Succinate was originally described as a metabolite that supports inflammation via distinct routes. Recently, studies have indicated that succinate and its receptor SUCNR1 can suppress immune responses as well. These apparent contradictory effects might be due to specific experimental settings and particularly the use of distinct succinate forms. We therefore compared the phenotypic and functional effects of distinct succinate forms and receptor mouse models that were previously used for studying succinate immunomodulation. Here, we show that succinate can suppress secretion of inflammatory mediators IL-6, tumor necrosis factor (TNF) and nitric oxide (NO), as well as inhibit Il1b mRNA expression of inflammatory macrophages in a SUCNR1-independent manner. We also observed that macrophage SUCNR1 deficiency led to an enhanced inflammatory response without addition of exogenous succinate. While our study does not reveal new mechanistic insights into how succinate elicits different inflammatory responses, it does indicate that the inflammatory effects of succinate and its receptor SUCNR1 in macrophages are clearly context dependent. Full article
(This article belongs to the Special Issue Regulation of Immunity and Inflammation by Immunometabolites and Metabolic Enzymes)
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20 pages, 2059 KiB  
Article
Metabolomic Profiling Reveals Distinct and Mutual Effects of Diet and Inflammation in Shaping Systemic Metabolism in Ldlr−/− Mice
by Mario A. Lauterbach, Eicke Latz and Anette Christ
Metabolites 2020, 10(9), 336; https://doi.org/10.3390/metabo10090336 - 19 Aug 2020
Cited by 4 | Viewed by 2216
Abstract
Changes in modern dietary habits such as consumption of Western-type diets affect physiology on several levels, including metabolism and inflammation. It is currently unclear whether changes in systemic metabolism due to dietary interventions are long-lasting and affect acute inflammatory processes. Here, we investigated [...] Read more.
Changes in modern dietary habits such as consumption of Western-type diets affect physiology on several levels, including metabolism and inflammation. It is currently unclear whether changes in systemic metabolism due to dietary interventions are long-lasting and affect acute inflammatory processes. Here, we investigated how high-fat diet (HFD) feeding altered systemic metabolism and the metabolomic response to inflammatory stimuli. We conducted metabolomic profiling of sera collected from Ldlr−/− mice on either regular chow diet (CD) or HFD, and after an additional low-dose lipopolysaccharide (LPS) challenge. HFD feeding, as well as LPS treatment, elicited pronounced metabolic changes. HFD qualitatively altered the systemic metabolic response to LPS; particularly, serum concentrations of fatty acids and their metabolites varied between LPS-challenged mice on HFD or CD, respectively. To investigate whether systemic metabolic changes were sustained long-term, mice fed HFD were shifted back to CD after four weeks (HFD > CD). When shifted back to CD, serum metabolites returned to baseline levels, and so did the response to LPS. Our results imply that systemic metabolism rapidly adapts to dietary changes. The profound systemic metabolic rewiring observed in response to diet might affect immune cell reprogramming and inflammatory responses. Full article
(This article belongs to the Special Issue Regulation of Immunity and Inflammation by Immunometabolites and Metabolic Enzymes)
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18 pages, 2259 KiB  
Article
Involvement of Lactate and Pyruvate in the Anti-Inflammatory Effects Exerted by Voluntary Activation of the Sympathetic Nervous System
by Jelle Zwaag, Rob ter Horst, Ivana Blaženović, Daniel Stoessel, Jacqueline Ratter, Josephine M. Worseck, Nicolas Schauer, Rinke Stienstra, Mihai G. Netea, Dieter Jahn, Peter Pickkers and Matthijs Kox
Metabolites 2020, 10(4), 148; https://doi.org/10.3390/metabo10040148 - 10 Apr 2020
Cited by 18 | Viewed by 26789
Abstract
We recently demonstrated that the sympathetic nervous system can be voluntarily activated following a training program consisting of cold exposure, breathing exercises, and meditation. This resulted in profound attenuation of the systemic inflammatory response elicited by lipopolysaccharide (LPS) administration. Herein, we assessed whether [...] Read more.
We recently demonstrated that the sympathetic nervous system can be voluntarily activated following a training program consisting of cold exposure, breathing exercises, and meditation. This resulted in profound attenuation of the systemic inflammatory response elicited by lipopolysaccharide (LPS) administration. Herein, we assessed whether this training program affects the plasma metabolome and if these changes are linked to the immunomodulatory effects observed. A total of 224 metabolites were identified in plasma obtained from 24 healthy male volunteers at six timepoints, of which 98 were significantly altered following LPS administration. Effects of the training program were most prominent shortly after initiation of the acquired breathing exercises but prior to LPS administration, and point towards increased activation of the Cori cycle. Elevated concentrations of lactate and pyruvate in trained individuals correlated with enhanced levels of anti-inflammatory interleukin (IL)-10. In vitro validation experiments revealed that co-incubation with lactate and pyruvate enhances IL-10 production and attenuates the release of pro-inflammatory IL-1β and IL-6 by LPS-stimulated leukocytes. Our results demonstrate that practicing the breathing exercises acquired during the training program results in increased activity of the Cori cycle. Furthermore, this work uncovers an important role of lactate and pyruvate in the anti-inflammatory phenotype observed in trained subjects. Full article
(This article belongs to the Special Issue Regulation of Immunity and Inflammation by Immunometabolites and Metabolic Enzymes)
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Review

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24 pages, 2572 KiB  
Review
Electrophile Modulation of Inflammation: A Two-Hit Approach
by James O’Brien and Stacy G. Wendell
Metabolites 2020, 10(11), 453; https://doi.org/10.3390/metabo10110453 - 10 Nov 2020
Cited by 4 | Viewed by 2846
Abstract
Electrophilic small molecules have gained significant attention over the last decade in the field of covalent drug discovery. Long recognized as mediators of the inflammatory process, recent evidence suggests that electrophiles may modulate the immune response through the regulation of metabolic networks. These [...] Read more.
Electrophilic small molecules have gained significant attention over the last decade in the field of covalent drug discovery. Long recognized as mediators of the inflammatory process, recent evidence suggests that electrophiles may modulate the immune response through the regulation of metabolic networks. These molecules function as pleiotropic signaling mediators capable of reversibly reacting with nucleophilic biomolecules, most notably at reactive cysteines. More specifically, electrophiles target critical cysteines in redox regulatory proteins to activate protective pathways such as the nuclear factor erythroid 2-related factor 2-Kelch-like ECH-associated protein 1 (Nrf2-Keap1) antioxidant signaling pathway while also inhibiting Nuclear Factor κB (NF-κB). During inflammatory states, reactive species broadly alter cell signaling through the oxidation of lipids, amino acids, and nucleic acids, effectively propagating the inflammatory sequence. Subsequent changes in metabolic signaling inform immune cell maturation and effector function. Therapeutic strategies targeting inflammatory pathologies leverage electrophilic drug compounds, in part, because of their documented effect on the redox balance of the cell. With mounting evidence demonstrating the link between redox signaling and metabolism, electrophiles represent ideal therapeutic candidates for the treatment of inflammatory conditions. Through their pleiotropic signaling activity, electrophiles may be used strategically to both directly and indirectly target immune cell metabolism. Full article
(This article belongs to the Special Issue Regulation of Immunity and Inflammation by Immunometabolites and Metabolic Enzymes)
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34 pages, 2074 KiB  
Review
Nitric Oxide in Macrophage Immunometabolism: Hiding in Plain Sight
by Erika M. Palmieri, Christopher McGinity, David A. Wink and Daniel W. McVicar
Metabolites 2020, 10(11), 429; https://doi.org/10.3390/metabo10110429 - 26 Oct 2020
Cited by 87 | Viewed by 8164
Abstract
Nitric Oxide (NO) is a soluble endogenous gas with various biological functions like signaling, and working as an effector molecule or metabolic regulator. In response to inflammatory signals, immune myeloid cells, like macrophages, increase production of cytokines and NO, which is important for [...] Read more.
Nitric Oxide (NO) is a soluble endogenous gas with various biological functions like signaling, and working as an effector molecule or metabolic regulator. In response to inflammatory signals, immune myeloid cells, like macrophages, increase production of cytokines and NO, which is important for pathogen killing. Under these proinflammatory circumstances, called “M1”, macrophages undergo a series of metabolic changes including rewiring of their tricarboxylic acid (TCA) cycle. Here, we review findings indicating that NO, through its interaction with heme and non-heme metal containing proteins, together with components of the electron transport chain, functions not only as a regulator of cell respiration, but also a modulator of intracellular cell metabolism. Moreover, diverse effects of NO and NO-derived reactive nitrogen species (RNS) involve precise interactions with different targets depending on concentration, temporal, and spatial restrictions. Although the role of NO in macrophage reprogramming has been in evidence for some time, current models have largely minimized its importance. It has, therefore, been hiding in plain sight. A review of the chemical properties of NO, past biochemical studies, and recent publications, necessitates that mechanisms of macrophage TCA reprogramming during stimulation must be re-imagined and re-interpreted as mechanistic results of NO exposure. The revised model of metabolic rewiring we describe here incorporates many early findings regarding NO biochemistry and brings NO out of hiding and to the forefront of macrophages immunometabolism. Full article
(This article belongs to the Special Issue Regulation of Immunity and Inflammation by Immunometabolites and Metabolic Enzymes)
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22 pages, 1188 KiB  
Review
The Role of Metabolic Enzymes in the Regulation of Inflammation
by Wesley H. Godfrey and Michael D. Kornberg
Metabolites 2020, 10(11), 426; https://doi.org/10.3390/metabo10110426 - 26 Oct 2020
Cited by 13 | Viewed by 3348
Abstract
Immune cells undergo dramatic metabolic reprogramming in response to external stimuli. These metabolic pathways, long considered as simple housekeeping functions, are increasingly understood to critically regulate the immune response, determining the activation, differentiation, and downstream effector functions of both lymphoid and myeloid cells. [...] Read more.
Immune cells undergo dramatic metabolic reprogramming in response to external stimuli. These metabolic pathways, long considered as simple housekeeping functions, are increasingly understood to critically regulate the immune response, determining the activation, differentiation, and downstream effector functions of both lymphoid and myeloid cells. Within the complex metabolic networks associated with immune activation, several enzymes play key roles in regulating inflammation and represent potential therapeutic targets in human disease. In some cases, these enzymes control flux through pathways required to meet specific energetic or metabolic demands of the immune response. In other cases, key enzymes control the concentrations of immunoactive metabolites with direct roles in signaling. Finally, and perhaps most interestingly, several metabolic enzymes have evolved moonlighting functions, with roles in the immune response that are entirely independent of their conventional enzyme activities. Here, we review key metabolic enzymes that critically regulate inflammation, highlighting mechanistic insights and opportunities for clinical intervention. Full article
(This article belongs to the Special Issue Regulation of Immunity and Inflammation by Immunometabolites and Metabolic Enzymes)
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18 pages, 1413 KiB  
Review
Metabolite Transporters as Regulators of Immunity
by Hauke J. Weiss and Stefano Angiari
Metabolites 2020, 10(10), 418; https://doi.org/10.3390/metabo10100418 - 19 Oct 2020
Cited by 19 | Viewed by 3676
Abstract
In the past decade, the rise of immunometabolism has fundamentally reshaped the face of immunology. As the functions and properties of many (immuno)metabolites have now been well described, their exchange among cells and their environment have only recently sparked the interest of immunologists. [...] Read more.
In the past decade, the rise of immunometabolism has fundamentally reshaped the face of immunology. As the functions and properties of many (immuno)metabolites have now been well described, their exchange among cells and their environment have only recently sparked the interest of immunologists. While many metabolites bind specific receptors to induce signaling cascades, some are actively exchanged between cells to communicate, or induce metabolic reprograming. In this review, we give an overview about how active metabolite transport impacts immune cell function and shapes immunological responses. We present some examples of how specific transporters feed into metabolic pathways and initiate intracellular signaling events in immune cells. In particular, we focus on the role of metabolite transporters in the activation and effector functions of T cells and macrophages, as prototype adaptive and innate immune cell populations. Full article
(This article belongs to the Special Issue Regulation of Immunity and Inflammation by Immunometabolites and Metabolic Enzymes)
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20 pages, 821 KiB  
Review
Molecular Chaperones: Molecular Assembly Line Brings Metabolism and Immunity in Shape
by Haoxin Zhao, Lydia N. Raines and Stanley Ching-Cheng Huang
Metabolites 2020, 10(10), 394; https://doi.org/10.3390/metabo10100394 - 03 Oct 2020
Cited by 7 | Viewed by 3700
Abstract
Molecular chaperones are a set of conserved proteins that have evolved to assist the folding of many newly synthesized proteins by preventing their misfolding under conditions such as elevated temperatures, hypoxia, acidosis and nutrient deprivation. Molecular chaperones belong to the heat shock protein [...] Read more.
Molecular chaperones are a set of conserved proteins that have evolved to assist the folding of many newly synthesized proteins by preventing their misfolding under conditions such as elevated temperatures, hypoxia, acidosis and nutrient deprivation. Molecular chaperones belong to the heat shock protein (HSP) family. They have been identified as important participants in immune functions including antigen presentation, immunostimulation and immunomodulation, and play crucial roles in metabolic rewiring and epigenetic circuits. Growing evidence has accumulated to indicate that metabolic pathways and their metabolites influence the function of immune cells and can alter transcriptional activity through epigenetic modification of (de)methylation and (de)acetylation. However, whether molecular chaperones can regulate metabolic programs to influence immune activity is still largely unclear. In this review, we discuss the available data on the biological function of molecular chaperones to immune responses during inflammation, with a specific focus on the interplay between molecular chaperones and metabolic pathways that drive immune cell fate and function. Full article
(This article belongs to the Special Issue Regulation of Immunity and Inflammation by Immunometabolites and Metabolic Enzymes)
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24 pages, 1548 KiB  
Review
Diverse Immunoregulatory Roles of Oxysterols—The Oxidized Cholesterol Metabolites
by Chloe Choi and David K. Finlay
Metabolites 2020, 10(10), 384; https://doi.org/10.3390/metabo10100384 - 28 Sep 2020
Cited by 30 | Viewed by 4917
Abstract
Intermediates of both cholesterol synthesis and cholesterol metabolism can have diverse roles in the control of cellular processes that go beyond the control of cholesterol homeostasis. For example, oxidized forms of cholesterol, called oxysterols have functions ranging from the control of gene expression, [...] Read more.
Intermediates of both cholesterol synthesis and cholesterol metabolism can have diverse roles in the control of cellular processes that go beyond the control of cholesterol homeostasis. For example, oxidized forms of cholesterol, called oxysterols have functions ranging from the control of gene expression, signal transduction and cell migration. This is of particular interest in the context of immunology and immunometabolism where we now know that metabolic processes are key towards shaping the nature of immune responses. Equally, aberrant metabolic processes including altered cholesterol homeostasis contribute to immune dysregulation and dysfunction in pathological situations. This review article brings together our current understanding of how oxysterols affect the control of immune responses in diverse immunological settings. Full article
(This article belongs to the Special Issue Regulation of Immunity and Inflammation by Immunometabolites and Metabolic Enzymes)
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15 pages, 1612 KiB  
Review
Regulatory T Cell Metabolism in Atherosclerosis
by Jeroen Baardman and Esther Lutgens
Metabolites 2020, 10(7), 279; https://doi.org/10.3390/metabo10070279 - 08 Jul 2020
Cited by 12 | Viewed by 3127
Abstract
Regulatory T cells (Tregs) are capable of suppressing excessive immune responses to prevent autoimmunity and chronic inflammation. Decreased numbers of Tregs and impaired suppressive function are associated with the progression of atherosclerosis, a chronic inflammatory disease of the arterial wall and the leading [...] Read more.
Regulatory T cells (Tregs) are capable of suppressing excessive immune responses to prevent autoimmunity and chronic inflammation. Decreased numbers of Tregs and impaired suppressive function are associated with the progression of atherosclerosis, a chronic inflammatory disease of the arterial wall and the leading cause of cardiovascular disease. Therefore, therapeutic strategies to improve Treg number or function could be beneficial to preventing atherosclerotic disease development. A growing body of evidence shows that intracellular metabolism of Tregs is a key regulator of their proliferation, suppressive function, and stability. Here we evaluate the role of Tregs in atherosclerosis, their metabolic regulation, and the links between their metabolism and atherosclerosis. Full article
(This article belongs to the Special Issue Regulation of Immunity and Inflammation by Immunometabolites and Metabolic Enzymes)
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