Metabolic reprogramming in macrophage responses

AbstractMacrophages are critical mediators of tissue homeostasis, with the function of tissue development and repair, but also in defense against pathogens. Tumor-associated macrophages (TAMs) are considered as the main component in the tumor microenvironment and play an important role in tumor initiation, growth, invasion, and metastasis. Recently, metabolic studies have revealeded specific metabolic pathways in macrophages are tightly associated with their phenotype and function. Generally, pro-inflammatory macrophages (M1) rely mainly on glycolysis and exhibit impairment of the tricarboxylic acid (TCA) cycle and mitochondrial oxidative phosphorylation (OXPHOS), whereas anti-inflammatory macrophages (M2) are more dependent on mitochondrial OXPHOS. However, accumulating evidence suggests that macrophage metabolism is not as simple as previously thought. This review discusses recent advances in immunometabolism and describes how metabolism determines macrophage phenotype and function. In addition, we describe the metabolic characteristics of TAMs as well as their therapeutic implications. Finally, we discuss recent obstacles facing this area as well as promising directions for future study.

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Metabolic Constants and Plasticity of Cancer Cells in a Limiting Glucose and Glutamine Microenvironment—A Pyruvate Perspective

Frontiers in Oncology ◽

10.3389/fonc.2020.596197 ◽

2020 ◽

Vol 10 ◽

Author(s):

Angela M. Otto

Keyword(s):

Cancer Cells ◽

Metabolic Network ◽

Metabolic Pathways ◽

Cancer Cell Line ◽

Tca Cycle ◽

Reaction Rates ◽

Diagnostic Methods ◽

Metabolic Reprogramming ◽

Amino Acid Synthesis ◽

The Tca Cycle

The metabolism of cancer cells is an issue of dealing with fluctuating and limiting levels of nutrients in a precarious microenvironment to ensure their vitality and propagation. Glucose and glutamine are central metabolites for catabolic and anabolic metabolism, which is in the limelight of numerous diagnostic methods and therapeutic targeting. Understanding tumor metabolism in conditions of nutrient depletion is important for such applications and for interpreting the readouts. To exemplify the metabolic network of tumor cells in a model system, the fate 13C6-glucose was tracked in a breast cancer cell line growing in variable low glucose/low glutamine conditions. 13C-glucose-derived metabolites allowed to deduce the engagement of metabolic pathways, namely glycolysis, the TCA-cycle including glutamine and pyruvate anaplerosis, amino acid synthesis (serine, glycine, aspartate, glutamate), gluconeogenesis, and pyruvate replenishment. While the metabolic program did not change, limiting glucose and glutamine supply reduced cellular metabolite levels and enhanced pyruvate recycling as well as pyruvate carboxylation for entry into the TCA-cycle. Otherwise, the same metabolic pathways, including gluconeogenesis, were similarly engaged with physiologically saturating as with limiting glucose and glutamine. Therefore, the metabolic plasticity in precarious nutritional microenvironment does not require metabolic reprogramming, but is based on dynamic changes in metabolite quantity, reaction rates, and directions of the existing metabolic network.

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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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Metabolic Adaptions/Reprogramming in Islet Beta-Cells in Response to Physiological Stimulators—What Are the Consequences

Antioxidants ◽

10.3390/antiox11010108 ◽

2022 ◽

Vol 11 (1) ◽

pp. 108

Author(s):

Philip Newsholme ◽

Jordan Rowlands ◽

Roselyn Rose’Meyer ◽

Vinicius Cruzat

Keyword(s):

Chronic Exposure ◽

Cell Damage ◽

Tca Cycle ◽

Metabolic Reprogramming ◽

Therapeutic Drug ◽

Inflammatory Factor ◽

Β Cell ◽

Regulatory Processes ◽

Drug Concentrations ◽

And Function

Irreversible pancreatic β-cell damage may be a result of chronic exposure to supraphysiological glucose or lipid concentrations or chronic exposure to therapeutic anti-diabetic drugs. The β-cells are able to respond to blood glucose in a narrow concentration range and release insulin in response, following activation of metabolic pathways such as glycolysis and the TCA cycle. The β-cell cannot protect itself from glucose toxicity by blocking glucose uptake, but indeed relies on alternative metabolic protection mechanisms to avoid dysfunction and death. Alteration of normal metabolic pathway function occurs as a counter regulatory response to high nutrient, inflammatory factor, hormone or therapeutic drug concentrations. Metabolic reprogramming is a term widely used to describe a change in regulation of various metabolic enzymes and transporters, usually associated with cell growth and proliferation and may involve reshaping epigenetic responses, in particular the acetylation and methylation of histone proteins and DNA. Other metabolic modifications such as Malonylation, Succinylation, Hydroxybutyrylation, ADP-ribosylation, and Lactylation, may impact regulatory processes, many of which need to be investigated in detail to contribute to current advances in metabolism. By describing multiple mechanisms of metabolic adaption that are available to the β-cell across its lifespan, we hope to identify sites for metabolic reprogramming mechanisms, most of which are incompletely described or understood. Many of these mechanisms are related to prominent antioxidant responses. Here, we have attempted to describe the key β-cell metabolic adaptions and changes which are required for survival and function in various physiological, pathological and pharmacological conditions.

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A Metabolic Reprogramming of Glycolysis and Glutamine Metabolism Is a Requisite for Renal Fibrogenesis—Why and How?

Frontiers in Physiology ◽

10.3389/fphys.2021.645857 ◽

2021 ◽

Vol 12 ◽

Author(s):

Timothy D. Hewitson ◽

Edward R. Smith

Keyword(s):

Wound Repair ◽

Regulatory Protein ◽

Cellular Metabolism ◽

Metabolic Reprogramming ◽

Glutamine Metabolism ◽

Protein Acetylation ◽

Mitochondrial Oxidative Phosphorylation ◽

And Function ◽

Renal Fibrogenesis ◽

Tgf Β1

Chronic Kidney Disease (CKD) is characterized by organ remodeling and fibrosis due to failed wound repair after on-going or severe injury. Key to this process is the continued activation and presence of matrix-producing renal fibroblasts. In cancer, metabolic alterations help cells to acquire and maintain a malignant phenotype. More recent evidence suggests that something similar occurs in the fibroblast during activation. To support these functions, pro-fibrotic signals released in response to injury induce metabolic reprograming to meet the high bioenergetic and biosynthetic demands of the (myo)fibroblastic phenotype. Fibrogenic signals such as TGF-β1 trigger a rewiring of cellular metabolism with a shift toward glycolysis, uncoupling from mitochondrial oxidative phosphorylation, and enhanced glutamine metabolism. These adaptations may also have more widespread implications with redirection of acetyl-CoA directly linking changes in cellular metabolism and regulatory protein acetylation. Evidence also suggests that injury primes cells to these metabolic responses. In this review we discuss the key metabolic events that have led to a reappraisal of the regulation of fibroblast differentiation and function in CKD.

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Recovery of Renal Function following Kidney-Specific VEGF Therapy in Experimental Renovascular Disease

American Journal of Nephrology ◽

10.1159/000511260 ◽

2020 ◽

Vol 51 (11) ◽

pp. 891-902

Author(s):

Jason E. Engel ◽

Maxx L. Williams ◽

Erika Williams ◽

Camille Azar ◽

Erin B. Taylor ◽

...

Keyword(s):

Renal Function ◽

Multidetector Ct ◽

Ex Vivo ◽

Macrophage Polarization ◽

Macrophage Phenotype ◽

Renovascular Disease ◽

Targeting Peptide ◽

And Function ◽

Inflammatory Macrophages

Background: Chronic renovascular disease (RVD) can lead to a progressive loss of renal function, and current treatments are inefficient. We designed a fusion of vascular endothelial growth factor (VEGF) conjugated to an elastin-like polypeptide (ELP) carrier protein with an N-terminal kidney-targeting peptide (KTP). We tested the hypothesis that KTP-ELP-VEGF therapy will effectively recover renal function with an improved targeting profile. Further, we aimed to elucidate potential mechanisms driving renal recovery. Methods: Unilateral RVD was induced in 14 pigs. Six weeks later, renal blood flow (RBF) and glomerular filtration rate (GFR) were quantified by multidetector CT imaging. Pigs then received a single intrarenal injection of KTP-ELP-VEGF or vehicle. CT quantification of renal hemodynamics was repeated 4 weeks later, and then pigs were euthanized. Ex vivo renal microvascular (MV) density and media-to-lumen ratio, macrophage infiltration, and fibrosis were quantified. In parallel, THP-1 human monocytes were differentiated into naïve macrophages (M0) or inflammatory macrophages (M1) and incubated with VEGF, KTP-ELP, KTP-ELP-VEGF, or control media. The mRNA expression of macrophage polarization and angiogenic markers was quantified (qPCR). Results: Intrarenal KTP-ELP-VEGF improved RBF, GFR, and MV density and attenuated MV media-to-lumen ratio and renal fibrosis compared to placebo, accompanied by augmented renal M2 macrophages. In vitro, exposure to VEGF/KTP-ELP-VEGF shifted M0 macrophages to a proangiogenic M2 phenotype while M1s were nonresponsive to VEGF treatment. Conclusions: Our results support the efficacy of a new renal-specific biologic construct in recovering renal function and suggest that VEGF may directly influence macrophage phenotype as a possible mechanism to improve MV integrity and function in the stenotic kidney.

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Harnessing Metabolic Reprogramming to Improve Cancer Immunotherapy

International Journal of Molecular Sciences ◽

10.3390/ijms221910268 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10268

Author(s):

Liang Yan ◽

Yanlian Tan ◽

Guo Chen ◽

Jun Fan ◽

Jun Zhang

Keyword(s):

Cancer Immunotherapy ◽

Immune Cells ◽

Metabolic Pathways ◽

Immune Escape ◽

Metabolic Reprogramming ◽

Immune Microenvironment ◽

Hallmarks Of Cancer ◽

Innovative Strategies ◽

Tumor Immune Microenvironment ◽

And Function

Immune escape is one of the hallmarks of cancer. While metabolic reprogramming provides survival advantage to tumor cancer cells, accumulating data also suggest such metabolic rewiring directly affects the activation, differentiation and function of immune cells, particularly in the tumor microenvironment. Understanding how metabolic reprogramming affects both tumor and immune cells, as well as their interplay, is therefore critical to better modulate tumor immune microenvironment in the era of cancer immunotherapy. In this review, we discuss alterations in several essential metabolic pathways in both tumor and key immune cells, provide evidence on their dynamic interaction, and propose innovative strategies to improve cancer immunotherapy via the modulation of metabolic pathways.

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Imaging the Rewired Metabolism in Lung Cancer in Relation to Immune Therapy

Frontiers in Oncology ◽

10.3389/fonc.2021.786089 ◽

2022 ◽

Vol 11 ◽

Author(s):

Evelien A. J. van Genugten ◽

Jetty A. M. Weijers ◽

Sandra Heskamp ◽

Manfred Kneilling ◽

Michel M. van den Heuvel ◽

...

Keyword(s):

Lung Cancer ◽

T Cells ◽

Tumor Microenvironment ◽

Cancer Cells ◽

Metabolic Pathways ◽

Immune Therapy ◽

Treatment Strategies ◽

Metabolic Reprogramming ◽

Metabolic Characteristics ◽

Starting Point

Metabolic reprogramming is recognized as one of the hallmarks of cancer. Alterations in the micro-environmental metabolic characteristics are recognized as important tools for cancer cells to interact with the resident and infiltrating T-cells within this tumor microenvironment. Cancer-induced metabolic changes in the micro-environment also affect treatment outcomes. In particular, immune therapy efficacy might be blunted because of somatic mutation-driven metabolic determinants of lung cancer such as acidity and oxygenation status. Based on these observations, new onco-immunological treatment strategies increasingly include drugs that interfere with metabolic pathways that consequently affect the composition of the lung cancer tumor microenvironment (TME). Positron emission tomography (PET) imaging has developed a wide array of tracers targeting metabolic pathways, originally intended to improve cancer detection and staging. Paralleling the developments in understanding metabolic reprogramming in cancer cells, as well as its effects on stromal, immune, and endothelial cells, a wave of studies with additional imaging tracers has been published. These tracers are yet underexploited in the perspective of immune therapy. In this review, we provide an overview of currently available PET tracers for clinical studies and discuss their potential roles in the development of effective immune therapeutic strategies, with a focus on lung cancer. We report on ongoing efforts that include PET/CT to understand the outcomes of interactions between cancer cells and T-cells in the lung cancer microenvironment, and we identify areas of research which are yet unchartered. Thereby, we aim to provide a starting point for molecular imaging driven studies to understand and exploit metabolic features of lung cancer to optimize immune therapy.

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Metabolic Changes of Hepatocytes in NAFLD

Frontiers in Physiology ◽

10.3389/fphys.2021.710420 ◽

2021 ◽

Vol 12 ◽

Author(s):

Qianrang Lu ◽

Xinyao Tian ◽

Hao Wu ◽

Jiacheng Huang ◽

Mengxia Li ◽

...

Keyword(s):

Metabolic Pathways ◽

Metabolic Disorders ◽

Lactate Production ◽

Atp Synthesis ◽

Tca Cycle ◽

Metabolic Changes ◽

Nonalcoholic Fatty Liver ◽

Metabolic Characteristics ◽

Body Production ◽

The Relationship

Nonalcoholic fatty liver disease (NAFLD) is often accompanied by systemic metabolic disorders such as hyperglycemia, insulin resistance, and obesity. The relationship between NAFLD and systemic metabolic disorders has been well reviewed before, however, the metabolic changes that occur in hepatocyte itself have not been discussed. In NAFLD, many metabolic pathways have undergone significant changes in hepatocyte, such as enhanced glycolysis, gluconeogenesis, lactate production, tricarboxylic acid (TCA) cycle, and decreased ketone body production, mitochondrial respiration, and adenosine triphosphate (ATP) synthesis, which play a role in compensating or exacerbating disease progression, and there is close and complex interaction existed between these metabolic pathways. Among them, some metabolic pathways can be the potential therapeutic targets for NAFLD. A detailed summary of the metabolic characteristics of hepatocytes in the context of NAFLD helps us better understand the pathogenesis and outcomes of the disease.

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Synthesis and Breakdown of the Universal Precursors to Biological Metabolism Promoted by Ferrous Iron

10.26434/chemrxiv.7178930.v1 ◽

2018 ◽

Cited By ~ 1

Author(s):

Kamila B. Muchowska ◽

Sreejith Jayasree VARMA ◽

Joseph Moran

Keyword(s):

Amino Acids ◽

Chemical Reaction ◽

Metabolic Pathways ◽

Ferrous Iron ◽

Reaction Network ◽

Tca Cycle ◽

Chemical Reaction Network ◽

Metabolic Precursors ◽

Tca Cycle Intermediates

How core biological metabolism initiated and why it uses the intermediates, reactions and pathways that it does remains unclear. Life builds its molecules from CO2 and breaks them down to CO2 again through the intermediacy of just five metabolites that act as the hubs of biochemistry. Here, we describe a purely chemical reaction network promoted by Fe2+ in which aqueous pyruvate and glyoxylate, two products of abiotic CO2 reduction, build up nine of the eleven TCA cycle intermediates, including all five universal metabolic precursors. The intermediates simultaneously break down to CO2 in a life-like regime resembling biological anabolism and catabolism. Introduction of hydroxylamine and Fe0 produces four biological amino acids. The network significantly overlaps the TCA/rTCA and glyoxylate cycles and may represent a prebiotic precursor to these core metabolic pathways.

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Arginase-2 is Essential for IL-10 Metabolic Reprogramming of Inflammatory Macrophages at the Mitochondria

SSRN Electronic Journal ◽

10.2139/ssrn.3554067 ◽

2020 ◽

Author(s):

Jennifer K. Dowling ◽

Remsha Afzal ◽

Linden J. Gearing ◽

Victoria G. Lyons ◽

Mariana P. Cervantes-Silva ◽

...

Keyword(s):

Metabolic Reprogramming ◽

Inflammatory Macrophages

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