Ironing out Macrophage Immunometabolism

Over the last decade, increasing evidence has reinforced the key role of metabolic reprogramming in macrophage activation. In addition to supporting the specific immune response of different subsets of macrophages, intracellular metabolic pathways also directly control the specialized effector functions of immune cells. In this context, iron metabolism has been recognized as an important component of macrophage plasticity. Since macrophages control the availability of this essential metal, changes in the expression of genes coding for the major proteins of iron metabolism may result in different iron availability for the macrophage itself and for other cells in the microenvironment. In this review, we discuss how macrophage iron can also play a role in immunometabolism.

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Iron Metabolism in the Tumor Microenvironment—Implications for Anti-Cancer Immune Response

Cells ◽

10.3390/cells10020303 ◽

2021 ◽

Vol 10 (2) ◽

pp. 303

Author(s):

Alessandro Sacco ◽

Anna Martina Battaglia ◽

Cirino Botta ◽

Ilenia Aversa ◽

Serafina Mancuso ◽

...

Keyword(s):

Tumor Microenvironment ◽

Iron Metabolism ◽

Immune Cells ◽

Metabolic Pathways ◽

Tumor Infiltrating Lymphocytes ◽

Oxygen Species ◽

Iron Availability ◽

Anti Cancer ◽

Immune Exclusion ◽

Infiltrating Lymphocytes

New insights into the field of iron metabolism within the tumor microenvironment have been uncovered in recent years. Iron promotes the production of reactive oxygen species, which may either trigger ferroptosis cell death or contribute to malignant transformation. Once transformed, cancer cells divert tumor-infiltrating immune cells to satisfy their iron demand, thus affecting the tumor immunosurveillance. In this review, we highlight how the bioavailability of this metal shapes complex metabolic pathways within the tumor microenvironment and how this affects both tumor-associated macrophages and tumor-infiltrating lymphocytes functions. Furthermore, we discuss the potentials as well as the current clinical controversies surrounding the use of iron metabolism as a target for new anticancer treatments in two opposed conditions: (i) the “hot” tumors, which are usually enriched in immune cells infiltration and are extremely rich in iron availability within the microenvironment, and (ii) the “cold” tumors, which are often very poor in immune cells, mainly due to immune exclusion.

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Role of dendritic cell metabolic reprogramming in tumor immune evasion

International Immunology ◽

10.1093/intimm/dxaa036 ◽

2020 ◽

Vol 32 (7) ◽

pp. 485-491 ◽

Cited By ~ 2

Author(s):

Michael P Plebanek ◽

Michael Sturdivant ◽

Nicholas C DeVito ◽

Brent A Hanks

Keyword(s):

Dendritic Cell ◽

Metabolic Pathways ◽

Checkpoint Inhibitor ◽

Therapeutic Strategies ◽

Metabolic Reprogramming ◽

Combination Immunotherapy ◽

Tumor Immune Evasion ◽

Effector T Cell ◽

Cell Responses

Abstract The dendritic cell (DC) is recognized as a vital mediator of anti-tumor immunity. More recent studies have also demonstrated the important role of DCs in the generation of effective responses to checkpoint inhibitor immunotherapy. Metabolic programming of DCs dictates their functionality and can determine which DCs become immunostimulatory versus those that develop a tolerized phenotype capable of actively suppressing effector T-cell responses to cancers. As a result, there is great interest in understanding what mechanisms have evolved in cancers to alter these metabolic pathways, thereby allowing for their continued progression and metastasis. The therapeutic strategies developed to reverse these processes of DC tolerization in the tumor microenvironment represent promising candidates for future testing in combination immunotherapy clinical trials.

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Immunometabolic hijacking of immune cells by a Pseudomonas aeruginosa quorum-sensing signal

10.1101/2021.10.03.462785 ◽

2021 ◽

Author(s):

Arunava Bandyopadhaya ◽

Vijay K Singh ◽

Arijit Chakraborty ◽

A. Aria Tzika ◽

Laurence G Rahme

Keyword(s):

Pseudomonas Aeruginosa ◽

Quorum Sensing ◽

Immune Cells ◽

Metabolic Pathways ◽

Metabolic Reprogramming ◽

Signal Molecule ◽

Host Immune Responses ◽

Pathogen Persistence ◽

Mitochondrial Pyruvate Carrier ◽

Inflammatory Milieu

AbstractMacrophages utilize metabolic pathways to generate energy and metabolites that may be vulnerable to pathogen hijacking to favor pathogen survival and persistence. It is unclear how bacterial pathogens alter metabolic pathways in immune cells for their benefit and persistence in the infected host. We have shown that the Pseudomonas aeruginosa quorum sensing (QS) signal molecule 2-aminoacetophenone (2-AA) allows pathogen persistence in host tissues by triggering host tolerization via histone deacetylase (HDAC)1-mediated epigenetic reprogramming. Here, we provide strong evidence that 2-AA-meditated persistence is linked to specific metabolic pathway alterations that reduce energy availability and biosynthetic macromolecules involved in host immune responses. 2-AA promotes a Warburg-like metabolic reprogramming effect, thereby increasing levels of lactate, which repressed inflammatory signaling in macrophages. Moreover, it interferes with pyruvate translocation to mitochondria, reducing mitochondrial (mt)-oxidative phosphorylation (OXPHOS) due to down-regulation of estrogen-regulated receptor (ERR)α and mitochondrial pyruvate carrier (MPC)-1. This metabolic reprogramming dampened energy production, reduced the acetyl-CoA pool, and generated an anti-inflammatory milieu that favors P. aeruginosa persistence. These findings provide evidence of first-in-class metabolic reprogramming in immune cells mediated by a QS signaling molecule. The specific metabolic programs affected provide insights that may guide the design and development of therapeutics and protective interventions against pathogen-induced immunometabolic alterations and persistence factors.

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The Role of Macrophages in Repair of Injured Myocardium and Perspectives of Metabolic Reprogramming of Immune Cells for Myocardial Post-Infarction Recovery

Kardiologiia ◽

10.18087/cardio.2017.12.10067 ◽

2017 ◽

Vol 17 (12) ◽

pp. 53-59 ◽

Cited By ~ 1

Author(s):

I. S. Stafeev ◽

◽

M. Y. Menshikov ◽

V. A. Tkachuk ◽

E. V. Parfenova ◽

...

Keyword(s):

Immune Cells ◽

Metabolic Reprogramming ◽

Injured Myocardium

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Minocycline Has Anti-inflammatory Effects and Reduces Cytotoxicity in an Ex Vivo Spinal Cord Slice Culture Model of West Nile Virus Infection

Journal of Virology ◽

10.1128/jvi.00569-17 ◽

2017 ◽

Vol 91 (22) ◽

Cited By ~ 13

Author(s):

Eamon D. Quick ◽

Scott Seitz ◽

Penny Clarke ◽

Kenneth L. Tyler

Keyword(s):

Spinal Cord ◽

West Nile Virus ◽

Immune Cells ◽

Microglial Activation ◽

Macrophage Activation ◽

Inflammatory Responses ◽

Ex Vivo ◽

West Nile ◽

Expression Of Genes ◽

Anti Inflammatory

ABSTRACT West Nile virus (WNV) is a neurotropic flavivirus that can cause significant neurological disease. Mouse models of WNV infection demonstrate that a proinflammatory environment is induced within the central nervous system (CNS) after WNV infection, leading to entry of activated peripheral immune cells. We utilized ex vivo spinal cord slice cultures (SCSC) to demonstrate that anti-inflammatory mechanisms may also play a role in WNV-induced pathology and/or recovery. Microglia are a type of macrophage that function as resident CNS immune cells. Similar to mouse models, infection of SCSC with WNV induces the upregulation of proinflammatory genes and proteins that are associated with microglial activation, including the microglial activation marker Iba1 and CC motif chemokines CCL2, CCL3, and CCL5. This suggests that microglia assume a proinflammatory phenotype in response to WNV infection similar to the proinflammatory (M1) activation that can be displayed by other macrophages. We now show that the WNV-induced expression of these and other proinflammatory genes was significantly decreased in the presence of minocycline, which has antineuroinflammatory properties, including the ability to inhibit proinflammatory microglial responses. Minocycline also caused a significant increase in the expression of anti-inflammatory genes associated with alternative anti-inflammatory (M2) macrophage activation, including interleukin 4 (IL-4), IL-13, and FIZZ1. Minocycline-dependent alterations to M1/M2 gene expression were associated with a significant increase in survival of neurons, microglia, and astrocytes in WNV-infected slices and markedly decreased levels of inducible nitric oxide synthase (iNOS). These results demonstrate that an anti-inflammatory environment induced by minocycline reduces viral cytotoxicity during WNV infection in ex vivo CNS tissue. IMPORTANCE West Nile virus (WNV) causes substantial morbidity and mortality, with no specific therapeutic treatments available. Antiviral inflammatory responses are a crucial component of WNV pathology, and understanding how they are regulated is important for tailoring effective treatments. Proinflammatory responses during WNV infection have been extensively studied, but anti-inflammatory responses (and their potential protective and reparative capabilities) following WNV infection have not been investigated. Minocycline induced the expression of genes associated with the anti-inflammatory (M2) activation of CNS macrophages (microglia) in WNV-infected SCSC while inhibiting the expression of genes associated with proinflammatory (M1) macrophage activation and was protective for multiple CNS cell types, indicating its potential use as a therapeutic reagent. This ex vivo culture system can uniquely address the ability of CNS parenchymal cells (neurons, astrocytes, and microglia) to respond to minocycline and to modulate the inflammatory environment and cytotoxicity in response to WNV infection without peripheral immune cell involvement.

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Pathogens MenTORing Macrophages and Dendritic Cells: Manipulation of mTOR and Cellular Metabolism to Promote Immune Escape

Cells ◽

10.3390/cells9010161 ◽

2020 ◽

Vol 9 (1) ◽

pp. 161 ◽

Cited By ~ 5

Author(s):

Lonneke V. Nouwen ◽

Bart Everts

Keyword(s):

Immune Response ◽

Dendritic Cells ◽

Amino Acid ◽

Immune Responses ◽

Metabolic Pathways ◽

Immune Escape ◽

Mammalian Target Of Rapamycin ◽

Metabolic Reprogramming ◽

First Line

Myeloid cells, including macrophages and dendritic cells, represent an important first line of defense against infections. Upon recognition of pathogens, these cells undergo a metabolic reprogramming that supports their activation and ability to respond to the invading pathogens. An important metabolic regulator of these cells is mammalian target of rapamycin (mTOR). During infection, pathogens use host metabolic pathways to scavenge host nutrients, as well as target metabolic pathways for subversion of the host immune response that together facilitate pathogen survival. Given the pivotal role of mTOR in controlling metabolism and DC and macrophage function, pathogens have evolved strategies to target this pathway to manipulate these cells. This review seeks to discuss the most recent insights into how pathogens target DC and macrophage metabolism to subvert potential deleterious immune responses against them, by focusing on the metabolic pathways that are known to regulate and to be regulated by mTOR signaling including amino acid, lipid and carbohydrate metabolism, and autophagy.

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Emergence of MicroRNAs as Key Players in Cancer Cell Metabolism

Clinical Chemistry ◽

10.1373/clinchem.2018.299651 ◽

2019 ◽

Vol 65 (9) ◽

pp. 1090-1101 ◽

Cited By ~ 17

Author(s):

Sugarniya Subramaniam ◽

Varinder Jeet ◽

Judith A Clements ◽

Jennifer H Gunter ◽

Jyotsna Batra

Keyword(s):

Fatty Acid ◽

Signaling Pathways ◽

Tumor Cells ◽

Metabolic Pathways ◽

Acid Metabolism ◽

Tca Cycle ◽

Metabolic Reprogramming ◽

Metabolic Adaptation ◽

Novel Therapeutic

AbstractBACKGROUNDMetabolic reprogramming is a hallmark of cancer. MicroRNAs (miRNAs) have been found to regulate cancer metabolism by regulating genes involved in metabolic pathways. Understanding this layer of complexity could lead to the development of novel therapeutic approaches.CONTENTmiRNAs are noncoding RNAs that have been implicated as master regulators of gene expression. Studies have revealed the role of miRNAs in the metabolic reprogramming of tumor cells, with several miRNAs both positively and negatively regulating multiple metabolic genes. The tricarboxylic acid (TCA) cycle, aerobic glycolysis, de novo fatty acid synthesis, and altered autophagy allow tumor cells to survive under adverse conditions. In addition, major signaling molecules, hypoxia-inducible factor, phosphatidylinositol-3 kinase/protein kinase B/mammalian target of rapamycin/phosphatase and tensin homolog, and insulin signaling pathways facilitate metabolic adaptation in tumor cells and are all regulated by miRNAs. Accumulating evidence suggests that miRNA mimics or inhibitors could be used to modulate the activity of miRNAs that drive tumor progression via altering their metabolism. Currently, several clinical trials investigating the role of miRNA-based therapy for cancer have been launched that may lead to novel therapeutic interventions in the future.SUMMARYIn this review, we summarize cancer-related metabolic pathways, including glycolysis, TCA cycle, pentose phosphate pathway, fatty acid metabolism, amino acid metabolism, and other metabolism-related oncogenic signaling pathways, and their regulation by miRNAs that are known to lead to tumorigenesis. Further, we discuss the current state of miRNA therapeutics in the clinic and their future potential.

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Cancer cell metabolic reprogramming: a keystone for the response to immunotherapy

Cell Death and Disease ◽

10.1038/s41419-020-03175-5 ◽

2020 ◽

Vol 11 (11) ◽

Cited By ~ 1

Author(s):

Michaël Cerezo ◽

Stéphane Rocchi

Keyword(s):

Tumor Microenvironment ◽

Immune Cells ◽

Metabolic Pathways ◽

Immune Checkpoint Inhibitors ◽

Antitumor Immunity ◽

Checkpoint Inhibitors ◽

Metabolic Reprogramming ◽

Limited Resources ◽

Antitumor Response ◽

Secondary Resistance

Abstract By targeting the tumor microenvironment to stimulate antitumor immunity, immunotherapies have revolutionized cancer treatment. However, many patients do not respond initially or develop secondary resistance. Based on the limited resources in the tumor microenvironment and competition between tumor and immune cells, the field of immune metabolism has produced extensive knowledge showing that targeting metabolism could help to modulate antitumor immunity. However, among all the different potentially targetable metabolic pathways, it remains unclear which have more potential to overcome resistance to immune checkpoint inhibitors. Here, we explore metabolic reprogramming in cancer cells, which might inhibit antitumor immunity, and strategies that can be used to favor the antitumor response.

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Mitochondrial Carriers and Substrates Transport Network: A Lesson from Saccharomyces cerevisiae

International Journal of Molecular Sciences ◽

10.3390/ijms22168496 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8496

Author(s):

Alessandra Ferramosca ◽

Vincenzo Zara

Keyword(s):

Saccharomyces Cerevisiae ◽

Metabolic Pathways ◽

Environmental Changes ◽

Human Cells ◽

Metabolic Reprogramming ◽

Model Organisms ◽

Mitochondrial Carrier ◽

Mitochondrial Carriers ◽

Functional Connections

The yeast Saccharomyces cerevisiae is one of the most widely used model organisms for investigating various aspects of basic cellular functions that are conserved in human cells. This organism, as well as human cells, can modulate its metabolism in response to specific growth conditions, different environmental changes, and nutrient depletion. This adaptation results in a metabolic reprogramming of specific metabolic pathways. Mitochondrial carriers play a fundamental role in cellular metabolism, connecting mitochondrial with cytosolic reactions. By transporting substrates across the inner membrane of mitochondria, they contribute to many processes that are central to cellular function. The genome of Saccharomyces cerevisiae encodes 35 members of the mitochondrial carrier family, most of which have been functionally characterized. The aim of this review is to describe the role of the so far identified yeast mitochondrial carriers in cell metabolism, attempting to show the functional connections between substrates transport and specific metabolic pathways, such as oxidative phosphorylation, lipid metabolism, gluconeogenesis, and amino acids synthesis. Analysis of the literature reveals that these proteins transport substrates involved in the same metabolic pathway with a high degree of flexibility and coordination. The understanding of the role of mitochondrial carriers in yeast biology and metabolism could be useful for clarifying unexplored aspects related to the mitochondrial carrier network. Such knowledge will hopefully help in obtaining more insight into the molecular basis of human diseases.

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Iron acquisition inLeishmaniaand its crucial role in infection

Parasitology ◽

10.1017/s0031182016000858 ◽

2016 ◽

Vol 143 (11) ◽

pp. 1347-1357 ◽

Cited By ~ 9

Author(s):

QINWANG NIU ◽

SHIHONG LI ◽

DALI CHEN ◽

QIWEI CHEN ◽

JIANPING CHEN

Keyword(s):

Free Radicals ◽

Iron Metabolism ◽

Metabolic Pathways ◽

Crucial Role ◽

Iron Acquisition ◽

Iron Limitation ◽

Iron Availability ◽

Acquisition Strategies ◽

Dual Character ◽

Pathogenic Microbes

SUMMARYIron is an essential cofactor for many basic metabolic pathways in pathogenic microbes and their hosts. It is also dangerous as it can catalyse the production of reactive free radicals. This dual character makes the host can either limit iron availability to invading microbes or exploit iron to induce toxicity to pathogens. Successful pathogens, includingLeishmaniaspecies, must possess mechanisms to circumvent host's iron limitation and iron-induced toxicity in order to survive. In this review, we discuss the regulation of iron metabolism in the setting of infection and delineate the iron acquisition strategies used byLeishmaniaparasites and their subversions to host iron metabolism to overcome host's iron-related defences.

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