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Frontiers in Immunology 2022Macrophages are essential innate immune cells that contribute to host defense during infection. An important feature of macrophages is their ability to respond to... (Review)
Review
Macrophages are essential innate immune cells that contribute to host defense during infection. An important feature of macrophages is their ability to respond to extracellular cues and to adopt different phenotypes and functions in response to these stimuli. The evidence accumulated in the last decade has highlighted the crucial role of metabolic reprogramming during macrophage activation in infectious context. Thus, understanding and manipulation of macrophage immunometabolism during infection could be of interest to develop therapeutic strategies. In this review, we focus on 5 major metabolic pathways including glycolysis, pentose phosphate pathway, fatty acid oxidation and synthesis, tricarboxylic acid cycle and amino acid metabolism and discuss how they sustain and regulate macrophage immune function in response to parasitic, bacterial and viral infections as well as trained immunity. At the end, we assess whether some drugs including those used in clinic and in development can target macrophage immunometabolism for potential therapy during infection with an emphasis on SARS-CoV2 infection.
Topics: Animals; COVID-19; Humans; Immunity, Innate; Infections; Macrophage Activation; Macrophages; SARS-CoV-2
PubMed: 35154105
DOI: 10.3389/fimmu.2022.780839 -
Frontiers in Immunology 2019Macrophage activation is intimately linked to metabolic reprogramming. Inflammatory (M1) macrophages are able to sustain inflammatory responses and to kill pathogens,... (Review)
Review
Macrophage activation is intimately linked to metabolic reprogramming. Inflammatory (M1) macrophages are able to sustain inflammatory responses and to kill pathogens, mostly by relying on aerobic glycolysis and fatty acid biosynthesis. Glycolysis is a fast way of producing ATP, and fatty acids serve as precursors for the synthesis of inflammatory mediators. On the opposite side, anti-inflammatory (M2) macrophages mediate the resolution of inflammation and tissue repair, switching their metabolism to fatty acid oxidation and oxidative phosphorylation. Over the years, this classical view has been challenged by recent discoveries pointing to a more complex metabolic network during macrophage activation. Lipid metabolism plays a critical role in the activation of both M1 and M2 macrophages. Recent evidence shows that fatty acid oxidation is also essential for inflammasome activation in M1 macrophages, and glycolysis is now known to fuel fatty acid oxidation in M2 macrophages. Ultimately, targeting lipid metabolism in macrophages can improve the outcome of metabolic diseases. Here, we review the main aspects of macrophage immunometabolism from the perspective of the metabolism of lipids. Building a reliable metabolic network during macrophage activation will bring us closer to targeting macrophages for improving human health.
Topics: Animals; Humans; Inflammation; Lipid Metabolism; Macrophage Activation; Macrophages; Metabolic Diseases
PubMed: 31998297
DOI: 10.3389/fimmu.2019.02993 -
Nature Reviews. Cardiology Apr 2020Monocytes and macrophages provide defence against pathogens and danger signals. These cells respond to stimulation in a fast and stimulus-specific manner by utilizing... (Review)
Review
Monocytes and macrophages provide defence against pathogens and danger signals. These cells respond to stimulation in a fast and stimulus-specific manner by utilizing complex cascaded activation by lineage-determining and signal-dependent transcription factors. The complexity of the functional response is determined by interactions between triggered transcription factors and depends on the microenvironment and interdependent signalling cascades. Dysregulation of macrophage phenotypes is a major driver of various diseases such as atherosclerosis, rheumatoid arthritis and type 2 diabetes mellitus. Furthermore, exposure of monocytes, which are macrophage precursor cells, to certain stimuli can lead to a hypo-inflammatory tolerized phenotype or a hyper-inflammatory trained phenotype in a macrophage. In atherosclerosis, macrophages and monocytes are exposed to inflammatory cytokines, oxidized lipids, cholesterol crystals and other factors. All these stimuli induce not only a specific transcriptional response but also interact extensively, leading to transcriptional and epigenetic heterogeneity of macrophages in atherosclerotic plaques. Targeting the epigenetic landscape of plaque macrophages can be a powerful therapeutic tool to modulate pro-atherogenic phenotypes and reduce the rate of plaque formation. In this Review, we discuss the emerging role of transcription factors and epigenetic remodelling in macrophages in the context of atherosclerosis and inflammation, and provide a comprehensive overview of epigenetic enzymes and transcription factors that are involved in macrophage activation.
Topics: Atherosclerosis; Epigenesis, Genetic; Macrophage Activation; Macrophages; Transcription, Genetic
PubMed: 31578516
DOI: 10.1038/s41569-019-0265-3 -
British Journal of Pharmacology Dec 2021Macrophage activation in response to stimulation of Toll-like receptor 4 (TLR4) provides a paradigm for investigating energy metabolism that regulates the inflammatory... (Review)
Review
Macrophage activation in response to stimulation of Toll-like receptor 4 (TLR4) provides a paradigm for investigating energy metabolism that regulates the inflammatory response. TLR4-mediated pro-inflammatory macrophage activation is characterized by increased glycolysis and altered mitochondrial metabolism, supported by selective amino acid uptake and/or usage. Fatty acid metabolism remains as a highly complex rewiring that accompanies classical macrophage activation. TLR4 activation leads to de novo synthesis of fatty acids, which flux into sphingolipids, complex lipids that form the building blocks of eukaryotic cell membranes and regulate cell function. Here, we review the importance of TLR4-mediated de novo synthesis of membrane sphingolipids in macrophages. We first highlight fatty acid metabolism during TLR4-driven macrophage immunometabolism. We then focus on the temporal dynamics of sphingolipid biosynthesis and emphasize the modulatory role of some sphingolipid species (i.e. sphingomyelins, ceramides and glycosphingolipids) on the pro-inflammatory and pro-resolution phases of LPS/TLR4 activation in macrophages.
Topics: Lipopolysaccharides; Macrophage Activation; Macrophages; Sphingolipids; Toll-Like Receptor 4
PubMed: 34363204
DOI: 10.1111/bph.15642 -
Science Immunology Apr 2022Macrophages populate every organ during homeostasis and disease, displaying features of tissue imprinting and heterogeneous activation. The disconnected picture of...
Macrophages populate every organ during homeostasis and disease, displaying features of tissue imprinting and heterogeneous activation. The disconnected picture of macrophage biology that has emerged from these observations is a barrier for integration across models or with in vitro macrophage activation paradigms. We set out to contextualize macrophage heterogeneity across mouse tissues and inflammatory conditions, specifically aiming to define a common framework of macrophage activation. We built a predictive model with which we mapped the activation of macrophages across 12 tissues and 25 biological conditions, finding a notable commonality and finite number of transcriptional profiles, in particular among infiltrating macrophages, which we modeled as defined stages along four conserved activation paths. These activation paths include a "phagocytic" regulatory path, an "inflammatory" cytokine-producing path, an "oxidative stress" antimicrobial path, or a "remodeling" extracellular matrix deposition path. We verified this model with adoptive cell transfer experiments and identified transient RELMɑ expression as a feature of monocyte-derived macrophage tissue engraftment. We propose that this integrative approach of macrophage classification allows the establishment of a common predictive framework of monocyte-derived macrophage activation in inflammation and homeostasis.
Topics: Animals; Cytokines; Homeostasis; Inflammation; Macrophage Activation; Macrophages; Mice
PubMed: 35427180
DOI: 10.1126/sciimmunol.abl7482 -
Immunity Nov 2021Alternatively activated macrophages (AAMs) contribute to the resolution of inflammation and tissue repair. However, molecular pathways that govern their differentiation...
Alternatively activated macrophages (AAMs) contribute to the resolution of inflammation and tissue repair. However, molecular pathways that govern their differentiation have remained incompletely understood. Here, we show that uncoupling protein-2-mediated mitochondrial reprogramming and the transcription factor GATA3 specifically controlled the differentiation of pro-resolving AAMs in response to the alarmin IL-33. In macrophages, IL-33 sequentially triggered early expression of pro-inflammatory genes and subsequent differentiation into AAMs. Global analysis of underlying signaling events revealed that IL-33 induced a rapid metabolic rewiring of macrophages that involved uncoupling of the respiratory chain and increased production of the metabolite itaconate, which subsequently triggered a GATA3-mediated AAM polarization. Conditional deletion of GATA3 in mononuclear phagocytes accordingly abrogated IL-33-induced differentiation of AAMs and tissue repair upon muscle injury. Our data thus identify an IL-4-independent and GATA3-dependent pathway in mononuclear phagocytes that results from mitochondrial rewiring and controls macrophage plasticity and the resolution of inflammation.
Topics: Biomarkers; Cell Differentiation; Energy Metabolism; Inflammation; Interleukin-33; Macrophage Activation; Macrophages; Mitochondria; Phagocytes; Signal Transduction
PubMed: 34644537
DOI: 10.1016/j.immuni.2021.09.010 -
Frontiers in Immunology 2022Macrophages play an important role in tissue homeostasis, tissue remodeling, immune response, and progression of cancer. Consequently, macrophages exhibit significant... (Review)
Review
Macrophages play an important role in tissue homeostasis, tissue remodeling, immune response, and progression of cancer. Consequently, macrophages exhibit significant plasticity and change their transcriptional profile and function in response to environmental, tissue, and inflammatory stimuli resulting in pro- and anti-tumor effects. Furthermore, the categorization of tissue macrophages in inflammatory situations remains difficult; however, there is an agreement that macrophages are predominantly polarized into two different subtypes with pro- and anti-inflammatory properties, the so-called M1-like and M2-like macrophages, respectively. These two macrophage classes can be considered as the extreme borders of a continuum of many intermediate subsets. On one end, M1 are pro-inflammatory macrophages that initiate an immunological response, damage tissue integrity, and dampen tumor progression by fostering robust T and natural killer (NK) cell anti-tumoral responses. On the other end, M2 are anti-inflammatory macrophages involved in tissue remodeling and tumor growth, that promote cancer cell proliferation, invasion, tumor metastasis, angiogenesis and that participate to immune suppression. These decisive roles in tumor progression occur through the secretion of cytokines, chemokines, growth factors, and matrix metalloproteases, as well as by the expression of immune checkpoint receptors in the case of M2 macrophages. Moreover, macrophage plasticity is supported by stimuli from the Tumor Microenvironment (TME) that are relayed to the nucleus through membrane receptors and signaling pathways that result in gene expression reprogramming in macrophages, thus giving rise to different macrophage polarization outcomes. In this review, we will focus on the main signaling pathways involved in macrophage polarization that are activated upon ligand-receptor recognition and in the presence of other immunomodulatory molecules in cancer.
Topics: Humans; Macrophage Activation; Macrophages; Neoplasms; Tumor Microenvironment; Signal Transduction
PubMed: 36325334
DOI: 10.3389/fimmu.2022.1026954 -
Frontiers in Immunology 2022Cardiovascular diseases, the notorious killer, are mainly caused by atherosclerosis (AS) characterized by lipids, cholesterol, and iron overload in plaques. Macrophages...
Cardiovascular diseases, the notorious killer, are mainly caused by atherosclerosis (AS) characterized by lipids, cholesterol, and iron overload in plaques. Macrophages are effector cells and accumulate to the damaged and inflamed sites of arteries to internalize native and chemically modified lipoproteins to transform them into cholesterol-loaded foam cells. Foam cell formation is determined by the capacity of phagocytosis, migration, scavenging, and the features of phenotypes. Macrophages are diverse, and the subsets and functions are controlled by their surrounding microenvironment. Generally, macrophages are divided into classically activated (M1) and alternatively activated (M2). Recently, intraplaque macrophage phenotypes are recognized by the stimulation of CXCL4 (M4), oxidized phospholipids (Mox), hemoglobin/haptoglobin complexes [HA-mac/M(Hb)], and heme (Mhem). The pro-atherogenic or anti-atherosclerotic phenotypes of macrophages decide the progression of AS. Besides, apoptosis, necrosis, ferroptosis, autophagy and pyrotopsis determine plaque formation and cardiovascular vulnerability, which may be associated with macrophage polarization phenotypes. In this review, we first summarize the three most popular hypotheses for AS and find the common key factors for further discussion. Secondly, we discuss the factors affecting macrophage polarization and five types of macrophage death in AS progression, especially ferroptosis. A comprehensive understanding of the cellular and molecular mechanisms of plaque formation is conducive to disentangling the candidate targets of macrophage-targeting therapies for clinical intervention at various stages of AS.
Topics: Atherosclerosis; Foam Cells; Humans; Macrophage Activation; Macrophages; Plaque, Atherosclerotic
PubMed: 35432323
DOI: 10.3389/fimmu.2022.843712 -
Molecular Cancer Feb 2021Noncoding RNA (ncRNA) transcripts that did not code proteins but regulate their functions were extensively studied for the last two decades and the plethora of... (Review)
Review
Noncoding RNA (ncRNA) transcripts that did not code proteins but regulate their functions were extensively studied for the last two decades and the plethora of discoveries have instigated scientists to investigate their dynamic roles in several diseases especially in cancer. However, there is much more to learn about the role of ncRNAs as drivers of malignant cell evolution in relation to macrophage polarization in the tumor microenvironment. At the initial stage of tumor development, macrophages have an important role in directing Go/No-go decisions to the promotion of tumor growth, immunosuppression, and angiogenesis. Tumor-associated macrophages behave differently as they are predominantly induced to be polarized into M2, a pro-tumorigenic type when recruited with the tumor tissue and thereby favoring the tumorigenesis. Polarization of macrophages into M1 or M2 subtypes plays a vital role in regulating tumor progression, metastasis, and clinical outcome, highlighting the importance of studying the factors driving this process. A substantial number of studies have demonstrated that ncRNAs are involved in the macrophage polarization based on their ability to drive M1 or M2 polarization and in this review we have described their functions and categorized them into oncogenes, tumor suppressors, Juggling tumor suppressors, and Juggling oncogenes.
Topics: Animals; Biomarkers, Tumor; Cell Plasticity; Disease Susceptibility; Gene Expression Regulation, Neoplastic; Humans; Macrophage Activation; Macrophages; MicroRNAs; Molecular Targeted Therapy; Neoplasms; RNA, Long Noncoding; RNA, Untranslated; Tumor Microenvironment
PubMed: 33522932
DOI: 10.1186/s12943-021-01313-x -
Neuroscience Jun 2020Inflammatory damage following ICH is often attributed to microglia/macrophage activation. In many diseases, IL-4 has been proven to switch microglia/macrophages from the...
Inflammatory damage following ICH is often attributed to microglia/macrophage activation. In many diseases, IL-4 has been proven to switch microglia/macrophages from the pro-inflammatory to the anti-inflammatory subtype. However, the role and underlying mechanism of IL-4 in ICH, especially in neuroprotection, remain unknown. In our study, we constructed a microglia/macrophage polarization model in BV2 cells to verify that the M2 shift of microglia/macrophages was mediated by JAK1/STAT6 after IL-4 treatment and then revealed that in vitro administration of IL-4 decreased M1 markers, pro-inflammatory cytokines and neuroapoptosis markers but significantly increased M2 markers and anti-inflammatory cytokines. Using an ICH model in mice, we observed that IL-4 administration decreased neurological deficits, brain edema and infarct lesions induced by ICH. We verified that IL-4 mediates inflammation by regulating M1/M2 polarization in ICH and explored the underlying mechanism. Furthermore, we discovered that pathway components and apoptosis-related proteins showed consistent trends based on their respective roles, and inferred that the process that TNF-α activates caspase-3 may be the crosstalk that microglia phagocytosis developed into accelerate apoptosis of cells in ICH. In conclusion, our study demonstrates that IL-4 may promote M2 microglia/macrophage polarization partly through the JAK1/STAT6 pathway to alleviate neuroinflammation after ICH.
Topics: Animals; Interleukin-4; Macrophage Activation; Macrophages; Mice; Microglia; Phagocytosis; STAT6 Transcription Factor
PubMed: 32224230
DOI: 10.1016/j.neuroscience.2020.03.008