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Metabolism Supports Macrophage Activation

Published on Jan 31, 2017in Frontiers in Immunology4.72
· DOI :10.3389/fimmu.2017.00061
P. Kent Langston1
Estimated H-index: 1
(Harvard University),
Munehiko Shibata4
Estimated H-index: 4
(Harvard University),
Tiffany Horng21
Estimated H-index: 21
(Harvard University)
Cite
Abstract
Macrophages are found in most tissues of the body, where they have tissue- and context-dependent roles in maintaining homeostasis as well as coordinating adaptive responses to a variety of stresses. Their capacity for specialized functions is controlled by polarizing signals, which activate (or polarize) macrophages by upregulating transcriptional programs that encode distinct effector functions. An important conceptual advance in the field of macrophage biology, emerging from recent studies, is that macrophage activation is critically supported by metabolic shifts. Metabolic shifts fuel multiple aspects of macrophage activation, and preventing these shifts impairs appropriate activation. These findings raise the exciting possibility that macrophage functions in various contexts could be regulated by manipulating their metabolism. Here we review the rapidly evolving field of macrophage metabolism, discussing how polarizing signals trigger metabolic shifts and how these shifts enable appropriate activation and sustain effector activities. We also discuss recent studies indicating that the mitochondria are central hubs in inflammatory macrophage activation.
  • References (43)
  • Citations (32)
Cite
References43
Newest
Published on Dec 1, 2016in Nature Communications11.88
Tetsuya Kimura37
Estimated H-index: 37
,
Shigeyuki Nada27
Estimated H-index: 27
+ 17 AuthorsYoshitomo Hayama5
Estimated H-index: 5
The role of nutrient-sensing pathways in regulation of innate immune response is unexplored. Here the authors show that IL-4 activates the amino-acid sensing pathway in macrophages and leads to polarization of anti-inflammatory M2 macrophages via the transcription factor liver X receptor.
Published on Nov 1, 2016in Nature Communications11.88
Gd Williams22
Estimated H-index: 22
(UTAS: University of Tasmania),
Laura Herraiz-Borreguero10
Estimated H-index: 10
(UCPH: University of Copenhagen)
+ 9 AuthorsClive R. McMahon33
Estimated H-index: 33
A fourth production region for the globally important Antarctic bottom water has been attributed to dense shelf water formation in the Cape Darnley Polynya, adjoining Prydz Bay in East Antarctica. Here we show new observations from CTD-instrumented elephant seals in 2011–2013 that provide the first complete assessment of dense shelf water formation in Prydz Bay. After a complex evolution involving opposing contributions from three polynyas (positive) and two ice shelves (negative), dense shelf w...
Published on Oct 1, 2016in Cell36.22
Evanna L. Mills9
Estimated H-index: 9
(Trinity College, Dublin),
Beth Kelly7
Estimated H-index: 7
(Trinity College, Dublin)
+ 17 AuthorsIsabel Latorre14
Estimated H-index: 14
(Harvard University)
Activated macrophages undergo metabolic reprogramming, which drives their pro-inflammatory phenotype, but the mechanistic basis for this remains obscure. Here, we demonstrate that upon lipopolysaccharide (LPS) stimulation, macrophages shift from producing ATP by oxidative phosphorylation to glycolysis while also increasing succinate levels. We show that increased mitochondrial oxidation of succinate via succinate dehydrogenase (SDH) and an elevation of mitochondrial membrane potential combine to...
Published on Oct 1, 2016in Immunity21.52
Stanley Ching-Cheng Huang20
Estimated H-index: 20
(WashU: Washington University in St. Louis),
Amber M. Smith28
Estimated H-index: 28
(WashU: Washington University in St. Louis)
+ 4 AuthorsEdward J. Pearce73
Estimated H-index: 73
(MPG: Max Planck Society)
Summary Macrophage activation status is intrinsically linked to metabolic remodeling. Macrophages stimulated by interleukin 4 (IL-4) to become alternatively (or, M2) activated increase fatty acid oxidation and oxidative phosphorylation; these metabolic changes are critical for M2 activation. Enhanced glucose utilization is also characteristic of the M2 metabolic signature. Here, we found that increased glucose utilization is essential for M2 activation. Increased glucose metabolism in IL-4-stimu...
Published on Sep 1, 2016in Nature Immunology23.53
M Zaeem Cader2
Estimated H-index: 2
(University of Cambridge),
Katharina Boroviak5
Estimated H-index: 5
(Wellcome Trust Sanger Institute)
+ 20 AuthorsSubhankar Mukhopadhyay19
Estimated H-index: 19
(Wellcome Trust Sanger Institute)
Supported by the European Research Council under the European Community’s Seventh Framework Programme (FP7/2007-2013)/ERC Grant agreement 260961, the Wellcome Trust (investigator award 106260/Z/14/Z; a PhD fellowship for clinicians; and a Career Re-Entry Fellowship), the Wellcome Trust Sanger Institute, the US National Institutes of Health (5U420D011174 and 5U54HG006348), the Biotechnology and Biological Sciences Research Council, the National Institute for Health Research Cambridge Biomedical R...
Published on Sep 1, 2016in Nature Immunology23.53
Johan Garaude13
Estimated H-index: 13
,
Rebeca Acín-Pérez30
Estimated H-index: 30
+ 8 AuthorsJosé Antonio Enríquez48
Estimated H-index: 48
Garaude and colleagues show that innate immunological sensing of live bacteria by macrophages elicits transient adaptations to the electron-transport chain of mitochondria.
Published on Jul 1, 2016in Cell Metabolism22.41
Vicky Lampropoulou15
Estimated H-index: 15
(WashU: Washington University in St. Louis),
Alexey Sergushichev13
Estimated H-index: 13
(WashU: Washington University in St. Louis)
+ 15 AuthorsTakla Griss9
Estimated H-index: 9
(McGill University)
Summary Remodeling of the tricarboxylic acid (TCA) cycle is a metabolic adaptation accompanying inflammatory macrophage activation. During this process, endogenous metabolites can adopt regulatory roles that govern specific aspects of inflammatory response, as recently shown for succinate, which regulates the pro-inflammatory IL-1β-HIF-1α axis. Itaconate is one of the most highly induced metabolites in activated macrophages, yet its functional significance remains unknown. Here, we show that ita...
Published on Jul 1, 2016in Journal of Biological Chemistry
Thekla Cordes9
Estimated H-index: 9
(UCSD: University of California, San Diego),
Martina Wallace15
Estimated H-index: 15
(UCSD: University of California, San Diego)
+ 8 AuthorsKarsten Hiller29
Estimated H-index: 29
(University of Luxembourg)
Abstract Metabolic reprogramming is emerging as a hallmark of the innate immune response, and the dynamic control of metabolites such as succinate serves to facilitate the execution of inflammatory responses in macrophages and other immune cells. Immunoresponsive gene 1 (Irg1) expression is induced by inflammatory stimuli, and its enzyme product cis-aconitate decarboxylase catalyzes the production of itaconate from the tricarboxylic acid cycle. Here we identify an immunometabolic regulatory path...
Published on Jun 1, 2016in Cell36.22
Michael D. Buck16
Estimated H-index: 16
(MPG: Max Planck Society),
David O'Sullivan11
Estimated H-index: 11
(MPG: Max Planck Society)
+ 16 AuthorsGerritje J.W. van der Windt11
Estimated H-index: 11
Summary Activated effector T (T E ) cells augment anabolic pathways of metabolism, such as aerobic glycolysis, while memory T (T M ) cells engage catabolic pathways, like fatty acid oxidation (FAO). However, signals that drive these differences remain unclear. Mitochondria are metabolic organelles that actively transform their ultrastructure. Therefore, we questioned whether mitochondrial dynamics controls T cell metabolism. We show that T E cells have punctate mitochondria, while T M cells main...
Published on Feb 19, 2016in eLife7.55
Anthony J. Covarrubias5
Estimated H-index: 5
(Harvard University),
Halil Aksoylar5
Estimated H-index: 5
(Harvard University)
+ 13 AuthorsTiffany Polynne-Stapornkul1
Estimated H-index: 1
(Harvard University)
Macrophages are immune cells that are found in most of the tissues of the body. Exactly what the macrophages do depends on which tissue they are in, and the state of the tissue. For example, M2 macrophages can multiply in numbers, heal wounds or help to fight off parasites depending on the signals they receive from their environment. Conversely, when macrophages sense pathogens such as bacteria they can also become M1 macrophages, which produce inflammatory molecules that help kill the invading ...
Cited By32
Newest
Published on Apr 11, 2019in Nature Communications11.88
Stephan Dreschers (RWTH Aachen University), Kim Ohl11
Estimated H-index: 11
(RWTH Aachen University)
+ 8 AuthorsJ. Roth84
Estimated H-index: 84
(WWU: University of Münster)
Neonatal sepsis is characterized by hyperinflammation causing enhanced morbidity and mortality compared to adults. This suggests differences in the response towards invading threats. Here we investigate activated cord blood macrophages (CBMΦ) in comparison to adult macrophages (PBMΦ), indicating incomplete interferon gamma (IFN-γ) and interleukin 10 (IL-10)-induced activation of CBMΦ. CBMΦ show reduced expression of phagocytosis receptors and cytokine expression in addition to altered energy met...
Published on Oct 1, 2019in Current Opinion in Immunology7.67
Matthew Knight1
Estimated H-index: 1
(University of California, Berkeley),
Sarah A. Stanley20
Estimated H-index: 20
(University of California, Berkeley)
Hypoxia-inducible transcription factor-1α (HIF-1α) was originally identified as a master regulator of cellular responses to hypoxia. More recently, HIF-1α has emerged as a critical regulator of immune cell function that couples shifts in cellular metabolism to cell type-specific transcriptional outputs. Activation of macrophages with inflammatory stimuli leads to induction of the metabolic program aerobic glycolysis and to HIF-1α stabilization, which reinforce one another in a positive feedback ...
Published on 2019in Nature Immunology23.53
P. Kent Langston1
Estimated H-index: 1
(Harvard University),
Aya Nambu1
Estimated H-index: 1
(Harvard University)
+ 7 AuthorsMichael R. MacArthur2
Estimated H-index: 2
(Harvard University)
Macrophages are activated during microbial infection to coordinate inflammatory responses and host defense. Here we find that in macrophages activated by bacterial lipopolysaccharide (LPS), mitochondrial glycerol 3-phosphate dehydrogenase (GPD2) regulates glucose oxidation to drive inflammatory responses. GPD2, a component of the glycerol phosphate shuttle, boosts glucose oxidation to fuel the production of acetyl coenzyme A, acetylation of histones and induction of genes encoding inflammatory m...
Published on Jun 1, 2019in Redox biology7.79
Chontida Yarana (MU: Mahidol University), Hannah Thompson (UK: University of Kentucky)+ 6 AuthorsDaret K. St. Clair59
Estimated H-index: 59
(UK: University of Kentucky)
Abstract Extracellular vesicles (EVs) generated from redox active anticancer drugs are released into the extracellular environment. These EVs contain oxidized molecules and trigger inflammatory responses by macrophages. Using a mouse model of doxorubicin (DOX)-induced tissue injury, we previously found that the major sources of circulating EVs are from heart and liver, organs that are differentially affected by DOX. Here, we investigated the effects of EVs from cardiomyocytes and those from hepa...
Published on Aug 21, 2019in bioRxiv
Duale Ahmed2
Estimated H-index: 2
(Carleton University),
David Roy1
Estimated H-index: 1
(Carleton University)
+ 5 AuthorsEdana Cassol14
Estimated H-index: 14
(Carleton University)
Increasing evidence suggests that mitochondria play a critical role in driving innate immune responses against bacteria and viruses. However, it is unclear if differential reprogramming of mitochondrial function contributes to the fine tuning of pathogen specific immune responses. Here, we found that TLR3 and TLR4 engagement on murine bone marrow derived macrophages was associated with differential remodeling of electron transport chain complex expression. This remodeling was associated with dif...
Published on Jan 1, 2019in Frontiers in Genetics3.52
Laura C. Miller14
Estimated H-index: 14
(ARS: Agricultural Research Service),
Damarius S. Fleming1
Estimated H-index: 1
(ORISE: Oak Ridge Institute for Science and Education)
Background: Porcine respiratory and reproductive syndrome virus (PRRSV) is a single stranded RNA virus member that infects pigs and causes losses to the commercial industry reaching upwards of a billion dollars annually in combined direct and indirect costs. The virus can be separated into etiologies that contain multiple heterologous low and highly pathogenic strains. Recently the United States has begun to see an increase in heterologous type 2 PRRSV strains of higher virulence (HP-PRRSV). The...
Published on Jul 1, 2019in Translational Oncology3.14
Abstract Let-7, a gene firstly known to control the timing of Caenorhabditis elegans larval development does not code for a protein but instead produces small non-coding RNAs, microRNAs. Higher animals have multiple isoforms of mature let-7 microRNAs. Mature let-7 family members share the same “seed sequence” and distinct from each other slightly by ‘non-seed’ sequence region. Let-7 has emerged as a central regulator of systemic energy homeostasis and it displays remarkable plasticity in metabol...
Published on Jul 1, 2019in Cytokine3.08
Bi Li (Sichuan Agricultural University), Jing Fang17
Estimated H-index: 17
(Sichuan Agricultural University)
+ 12 AuthorsYanchun Hu10
Estimated H-index: 10
(Sichuan Agricultural University)
Abstract Resistin is a cysteine-rich cytokine, which has been indicated as a mediator of insulin resistance and inflammation. Previous studies demonstrated that lipoprotein lipase (LPL) was an important enzyme that could mediate lipid accumulation in macrophages. Additionally, the intracellular molecules phosphatidylinositol 3-kinase (PI3K)/serine-threonine protein kinase (AKT)/peroxisome proliferator-activated receptor (PPARγ) were supposed to be involved in the lipid accumulation process in ce...
Published on Jun 19, 2019in Pharmaceuticals
Stefania Recalcati28
Estimated H-index: 28
,
Elena Gammella12
Estimated H-index: 12
,
Gaetano Cairo42
Estimated H-index: 42
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, chang...
View next paperSuccinate is an inflammatory signal that induces IL-1β through HIF-1α