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EMBO Reports Sep 2021Macrophages react to microbial and endogenous danger signals by activating a broad panel of effector and homeostatic responses. Such responses entail rapid and... (Review)
Review
Macrophages react to microbial and endogenous danger signals by activating a broad panel of effector and homeostatic responses. Such responses entail rapid and stimulus-specific changes in gene expression programs accompanied by extensive rewiring of metabolism, with alterations in chromatin modifications providing one layer of integration of transcriptional and metabolic regulation. A systematic and mechanistic understanding of the mutual influences between signal-induced metabolic changes and gene expression is still lacking. Here, we discuss current evidence, controversies, knowledge gaps, and future areas of investigation on how metabolic and transcriptional changes are dynamically integrated during macrophage activation. The cross-talk between metabolism and inflammatory gene expression is in part accounted for by alterations in the production, usage, and availability of metabolic intermediates that impact the macrophage epigenome. In addition, stimulus-inducible gene expression changes alter the production of inflammatory mediators, such as nitric oxide, that in turn modulate the activity of metabolic enzymes thus determining complex regulatory loops. Critical issues remain to be understood, notably whether and how metabolic rewiring can bring about gene-specific (as opposed to global) expression changes.
Topics: Gene Expression; Gene Expression Regulation; Humans; Inflammation; Macrophage Activation; Macrophages
PubMed: 34328708
DOI: 10.15252/embr.202153251 -
Immunity May 2017Recognition of pathogens by innate and adaptive immune cells instructs rapid alterations of cellular processes to promote effective resolution of infection. To... (Review)
Review
Recognition of pathogens by innate and adaptive immune cells instructs rapid alterations of cellular processes to promote effective resolution of infection. To accommodate increased bioenergetic and biosynthetic demands, metabolic pathways are harnessed to maximize proliferation and effector molecule production. In parallel, activation initiates context-specific gene-expression programs that drive effector functions and cell fates that correlate with changes in epigenetic landscapes. Many chromatin- and DNA-modifying enzymes make use of substrates and cofactors that are intermediates of metabolic pathways, providing potential cross talk between metabolism and epigenetic regulation of gene expression. In this review, we discuss recent studies of T cells and macrophages supporting a role for metabolic activity in integrating environmental signals with activation-induced gene-expression programs through modulation of the epigenome and speculate as to how this may influence context-specific macrophage and T cell responses to infection.
Topics: Animals; Cell Differentiation; Cellular Microenvironment; Energy Metabolism; Epigenesis, Genetic; Gene Expression Regulation; Humans; Immunity; Lymphocyte Activation; Macrophage Activation; Macrophages; Metabolic Networks and Pathways; T-Lymphocytes
PubMed: 28514673
DOI: 10.1016/j.immuni.2017.04.016 -
Frontiers in Immunology 2023Pain imposes a significant urden on patients, affecting them physically, psychologically, and economically. Despite numerous studies on the pathogenesis of pain, its... (Review)
Review
Pain imposes a significant urden on patients, affecting them physically, psychologically, and economically. Despite numerous studies on the pathogenesis of pain, its clinical management remains suboptimal, leading to the under-treatment of many pain patients. Recently, research on the role of macrophages in pain processes has been increasing, offering potential for novel therapeutic approaches. Macrophages, being indispensable immune cells in the innate immune system, exhibit remarkable diversity and plasticity. However, the majority of research has primarily focused on the contributions of M1 macrophages in promoting pain. During the late stage of tissue damage or inflammatory invasion, M1 macrophages typically transition into M2 macrophages. In recent years, growing evidence has highlighted the role of M2 macrophages in pain relief. In this review, we summarize the mechanisms involved in M2 macrophage polarization and discuss their emerging roles in pain relief. Notably, M2 macrophages appear to be key players in multiple endogenous pathways that promote pain relief. We further analyze potential pathways through which M2 macrophages may alleviate pain.
Topics: Humans; Pain Management; Pain; Macrophages; Macrophage Activation
PubMed: 37705982
DOI: 10.3389/fimmu.2023.1243149 -
Clinics and Research in Hepatology and... Sep 2015Macrophages are a key cell type in the innate immune system, and its proinflammatory (M1) activation in the liver plays a critical role in pathogenesis of alcoholic... (Review)
Review
Macrophages are a key cell type in the innate immune system, and its proinflammatory (M1) activation in the liver plays a critical role in pathogenesis of alcoholic steatohepatitis. Emerging evidence indicates the involvement of Notch signaling in regulation of innate immune response and cellular metabolism. Metabolic switch to glycolysis characterizes macrophages undergoing M1 activation. It has been proposed that metabolic reprograming in response to extrinsic stimulation, such as bacterial endotoxin, triggers intrinsic signal to dictate cell differentiation. Using an obesity-alcohol synergistic ASH mouse model, we have recently shown that Notch1 pathway promotes M1 activation of hepatic macrophages, through direct upregulation of M1 gene transcription and through reprograming of mitochondrial metabolism to glucose oxidation and subsequent mtROS generation to augment M1 gene expression. Our studies demonstrate a novel mechanism of Notch1 signaling in metabolic reprograming of macrophage for M1 activation in ASH.
Topics: Animals; Ethanol; Fatty Liver; Glucose; Humans; Liver; Macrophage Activation; Macrophages; Mitochondria, Liver; Obesity; Reactive Oxygen Species; Receptors, Notch; Signal Transduction
PubMed: 26189984
DOI: 10.1016/j.clinre.2015.05.016 -
Seminars in Immunopathology Sep 2019Emerging evidence suggest that macrophage and osteoclast are two competing differentiation outcomes from myeloid progenitors. In this review, we summarize recent... (Review)
Review
Emerging evidence suggest that macrophage and osteoclast are two competing differentiation outcomes from myeloid progenitors. In this review, we summarize recent advances in the understanding of the molecular mechanisms controlling the polarization of macrophage and osteoclast. These include nuclear receptors/transcription factors such as peroxisome proliferator-activated receptor γ (PPARγ) and estrogen-related receptor α (ERRα), their transcription cofactor PPARγ coactivator 1-β (PGC-1β), metabolic factors such as mitochondrial complex I (CI) component NADH:ubiquinone oxidoreductase iron-sulfur protein 4 (Ndufs4), as well as transmembrane receptors such as very-low-density-lipoprotein receptor (VLDLR). These molecular rheostats promote osteoclast differentiation but suppress proinflammatory macrophage activation and inflammation, by acting lineage-intrinsically, systemically or cross generation. These findings provide new insights to the understanding of the interactions between innate immunity and bone remodeling, advancing the field of osteoimmunology.
Topics: Animals; Biomarkers; Bone and Bones; Humans; Immunomodulation; Macrophage Activation; Macrophages; Osteoclasts; Osteogenesis; Osteoprotegerin; PPAR gamma; RANK Ligand; RNA-Binding Proteins; Receptor Activator of Nuclear Factor-kappa B; Receptors, Estrogen; Receptors, LDL; Signal Transduction; ERRalpha Estrogen-Related Receptor
PubMed: 31506868
DOI: 10.1007/s00281-019-00754-3 -
Frontiers in Immunology 2022Macrophages are highly plastic cells, and the polarization-activating actions that represent their functional focus are closely related to metabolic reprogramming. The... (Review)
Review
Macrophages are highly plastic cells, and the polarization-activating actions that represent their functional focus are closely related to metabolic reprogramming. The metabolic reprogramming of macrophages manifests itself as a bias toward energy utilization, transforming their inflammatory phenotype by changing how they use energy. Metabolic reprogramming effects crosstalk with the biological processes of inflammatory action and are key to the inflammatory function of macrophages. In ischemic heart disease, phenotypic polarization and metabolic shifts in circulating recruitment and tissue-resident macrophages can influence the balance of inflammatory effects in the heart and determine disease regression and prognosis. In this review, we present the intrinsic link between macrophage polarization and metabolic reprogramming, discussing the factors that regulate macrophages in the inflammatory effects of ischemic heart disease. Our aim is to estabilsh reliable regulatory pathways that will allow us to better target the macrophage metabolic reprogramming process and improve the symptoms of ischemic heart disease.
Topics: Humans; Macrophage Activation; Macrophages; Myocardial Ischemia; Phenotype
PubMed: 35924253
DOI: 10.3389/fimmu.2022.934040 -
BMB Reports Jun 2019Macrophages play an essential role not only in mediating the first line of defense but also in maintaining tissue homeostasis. In response to extrinsic factors derived... (Review)
Review
Macrophages play an essential role not only in mediating the first line of defense but also in maintaining tissue homeostasis. In response to extrinsic factors derived from a given tissue, macrophages activate different functional programs to produce polarized macrophage populations responsible for inducing inflammation against microbes, removing cellular debris, and tissue repair. However, accumulating evidence has revealed that macrophage polarization is pivotal in the pathophysiology of metabolic syndromes and cancer, as well as in infectious and autoimmune diseases. Recent advances in transcriptomic and metabolomic studies have highlighted the link between metabolic rewiring of macrophages and their functional plasticity. These findings imply that metabolic adaption to their surrounding microenvironment instructs activation of macrophages with functionally distinct phenotypes, which in turn probably leads to the pathogenesis of a wide spectrum of diseases. In this review, we have introduced emerging concepts in immunometabolism with focus on the impact on functional activation of macrophages. Furthermore, we have discussed the implication of macrophage plasticity on the pathogenesis of metabolic syndromes and cancer, and how the disease microenvironment manipulates macrophage metabolism with regard to the pathophysiology. [BMB Reports 2019; 52(6): 360-372].
Topics: Atherosclerosis; Cell Polarity; Homeostasis; Humans; Immunomodulation; Inflammation; Macrophage Activation; Macrophages; Neoplasms; Obesity; Phenotype
PubMed: 31186085
DOI: 10.5483/BMBRep.2019.52.6.140 -
Methods in Molecular Biology (Clifton,... 2021The immune system depends on two major paths-the innate and the adaptive immunity. Macrophage, with its unique features as the first line of immune defense to engulf and...
The immune system depends on two major paths-the innate and the adaptive immunity. Macrophage, with its unique features as the first line of immune defense to engulf and digest invaders, serves as the key effector cells integrating those two paths. The dynamic plasticity of macrophage activation during wound repair, inflammation resolution, and tissue remodeling are emerging biomedical and bioengineering hot topics in immune function studies such as the various secretions of cytokines and chemokines and the signaling pathways with ligands and their cognate receptors. Better knowledge on how physical/mechanical and multicellular microenvironment on the modulation of macrophage functions will create innovative therapies to boost host defense mechanism and assist wound healing. In this, we describe an easy method to measure functions (gene expressions) of human and mouse macrophages in response to mechanical microenvironment changes by embedding isolated macrophages in polymerized hyaluronan gel with different wound matrix stiffness.
Topics: Adaptive Immunity; Animals; Cytokines; Humans; Hyaluronic Acid; Inflammation; Macrophage Activation; Macrophages; Mice; Molecular Biology; Signal Transduction; Wound Healing
PubMed: 32808263
DOI: 10.1007/978-1-0716-0845-6_11 -
Nature Immunology Jan 2016In tissues, macrophages are exposed to metabolic, homeostatic and immunoregulatory signals of local or systemic origin that influence their basal functions and responses... (Review)
Review
In tissues, macrophages are exposed to metabolic, homeostatic and immunoregulatory signals of local or systemic origin that influence their basal functions and responses to danger signals. Signal-transduction pathways regulated by extracellular signals are coupled to distinct sets of broadly expressed stimulus-regulated transcription factors whose ability to elicit gene-expression changes is influenced by the accessibility of their binding sites in the macrophage genome. In turn, accessibility of macrophage-specific transcriptional regulatory elements (enhancers and promoters) is specified by transcription factors that determine the macrophage lineage or impose their tissue-specific properties. Here we review recent findings that advance the understanding of mechanisms underlying priming and signal-dependent activation of macrophages and discuss the effect of genetic variation on these processes.
Topics: Animals; Epigenesis, Genetic; Gene Expression Regulation; Humans; Macrophage Activation; Macrophages; Signal Transduction
PubMed: 26681459
DOI: 10.1038/ni.3306 -
Circulation Jan 2019
Topics: Humans; Indican; Macrophage Activation; Macrophages; Signal Transduction; Toxins, Biological; Uremia
PubMed: 30592654
DOI: 10.1161/CIRCULATIONAHA.118.037308