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Frontiers in Immunology 2023Macrophages are highly heterogeneous and plastic, and have two main polarized phenotypes that are determined by their microenvironment, namely pro- and anti-inflammatory... (Review)
Review
Macrophages are highly heterogeneous and plastic, and have two main polarized phenotypes that are determined by their microenvironment, namely pro- and anti-inflammatory macrophages. Activation of pro-inflammatory macrophages is closely associated with metabolic reprogramming, especially that of aerobic glycolysis. Mitochondrial pyruvate dehydrogenase kinase (PDK) negatively regulates pyruvate dehydrogenase complex activity through reversible phosphorylation and further links glycolysis to the tricarboxylic acid cycle and ATP production. PDK is commonly associated with the metabolism and polarization of macrophages in metabolic and inflammatory diseases. This review examines the relationship between PDK and macrophage metabolism and discusses the mechanisms by which PDK regulates macrophage polarization, migration, and inflammatory cytokine secretion in metabolic and inflammatory diseases. Elucidating the relationships between the metabolism and polarization of macrophages under physiological and pathological conditions, as well as the regulatory pathways involved, may provide valuable insights into the etiology and treatment of macrophage-mediated inflammatory diseases.
Topics: Pyruvate Dehydrogenase Acetyl-Transferring Kinase; Phosphorylation; Citric Acid Cycle; Macrophage Activation; Macrophages
PubMed: 38193078
DOI: 10.3389/fimmu.2023.1296687 -
Inflammation Research : Official... Jan 2024Emerging studies have revealed that macrophages possess different dependences on the uptake, synthesis, and metabolism of serine for their activation and... (Review)
Review
OBJECTIVE
Emerging studies have revealed that macrophages possess different dependences on the uptake, synthesis, and metabolism of serine for their activation and functionalization, necessitating our insight into how serine availability and utilization impact macrophage activation and inflammatory responses.
METHODS
This article summarizes the reports published domestically and internationally about the serine uptake, synthesis, and metabolic flux by the macrophages polarizing with distinct stimuli and under different pathologic conditions, and particularly analyzes how altered serine metabolism rewires the metabolic behaviors of polarizing macrophages and their genetic and epigenetic reprogramming.
RESULTS
Macrophages dynamically change serine metabolism to orchestrate their anabolism, redox balance, mitochondrial function, epigenetics, and post-translation modification, and thus match the distinct needs for both classical and alternative activation.
CONCLUSION
Serine metabolism coordinates multiple metabolic pathways to tailor macrophage polarization and their responses to different pathogenic attacks and thus holds the potential as therapeutic target for types of acute and chronic inflammatory diseases.
Topics: Macrophage Activation; Macrophages; Metabolic Networks and Pathways; Epigenesis, Genetic
PubMed: 38070057
DOI: 10.1007/s00011-023-01815-y -
Trends in Immunology Sep 2019Macrophages are important mediators of inflammation and tissue remodeling. Recent insights into the heterogeneity of macrophage subpopulations have renewed interest in... (Review)
Review
Macrophages are important mediators of inflammation and tissue remodeling. Recent insights into the heterogeneity of macrophage subpopulations have renewed interest in their functional diversity in homeostasis and disease. In addition, their plasticity enables them to perform a variety of functions in response to changing tissue contexts, such as those imposed by aging. These qualities make macrophages particularly intriguing cells given their dichotomous role in protecting against, or accelerating, diseases of the cardiovascular system and the eye, two tissues that are particularly susceptible to the effects of aging. We review novel perspectives on macrophage biology, as informed by recent studies detailing the diversity of macrophage identity and function, as well as mechanisms influencing macrophage behavior that might offer opportunities for new therapeutic strategies.
Topics: Aging; Animals; Cardiovascular Diseases; Cell Plasticity; Eye Diseases; Homeostasis; Humans; Macrophage Activation; Macrophages
PubMed: 31422901
DOI: 10.1016/j.it.2019.07.002 -
Frontiers in Immunology 2023Macrophages, as central components of innate immunity, feature significant heterogeneity. Numerus studies have revealed the pivotal roles of macrophages in the... (Review)
Review
Macrophages, as central components of innate immunity, feature significant heterogeneity. Numerus studies have revealed the pivotal roles of macrophages in the pathogenesis of liver fibrosis induced by various factors. Hepatic macrophages function to trigger inflammation in response to injury. They induce liver fibrosis by activating hepatic stellate cells (HSCs), and then inflammation and fibrosis are alleviated by the degradation of the extracellular matrix and release of anti-inflammatory cytokines. MicroRNAs (miRNAs), a class of small non-coding endogenous RNA molecules that regulate gene expression through translation repression or mRNA degradation, have distinct roles in modulating macrophage activation, polarization, tissue infiltration, and inflammation regression. Considering the complex etiology and pathogenesis of liver diseases, the role and mechanism of miRNAs and macrophages in liver fibrosis need to be further clarified. We first summarized the origin, phenotypes and functions of hepatic macrophages, then clarified the role of miRNAs in the polarization of macrophages. Finally, we comprehensively discussed the role of miRNAs and macrophages in the pathogenesis of liver fibrotic disease. Understanding the mechanism of hepatic macrophage heterogeneity in various types of liver fibrosis and the role of miRNAs on macrophage polarization provides a useful reference for further research on miRNA-mediated macrophage polarization in liver fibrosis, and also contributes to the development of new therapies targeting miRNA and macrophage subsets for liver fibrosis.
Topics: Humans; MicroRNAs; Macrophage Activation; Liver Cirrhosis; Liver Diseases; Macrophages; Inflammation
PubMed: 37138859
DOI: 10.3389/fimmu.2023.1147710 -
Cell Reports. Medicine Dec 2023Macrophage Clever-1 contributes to impaired antigen presentation and suppression of anti-tumor immunity. This first-in-human trial investigates the safety and...
Macrophage Clever-1 contributes to impaired antigen presentation and suppression of anti-tumor immunity. This first-in-human trial investigates the safety and tolerability of Clever-1 blockade with bexmarilimab in patients with treatment-refractory solid tumors and assesses preliminary anti-tumor efficacy, pharmacodynamics, and immunologic correlates. Bexmarilimab shows no dose-limiting toxicities in part I (n = 30) and no additional safety signals in part II (n = 108). Disease control (DC) rates of 25%-40% are observed in cutaneous melanoma, gastric, hepatocellular, estrogen receptor-positive breast, and biliary tract cancers. DC associates with improved survival in a landmark analysis and correlates with high pre-treatment intratumoral Clever-1 positivity and increasing on-treatment serum interferon γ (IFNγ) levels. Spatial transcriptomics profiling of DC and non-DC tumors demonstrates bexmarilimab-induced macrophage activation and stimulation of IFNγ and T cell receptor signaling selectively in DC patients. These data suggest that bexmarilimab therapy is well tolerated and show that macrophage targeting can promote immune activation and tumor control in late-stage cancer.
Topics: Humans; Antibodies, Monoclonal, Humanized; Macrophage Activation; Neoplasms
PubMed: 38056464
DOI: 10.1016/j.xcrm.2023.101307 -
Biochemical Society Transactions Dec 2022Atherosclerosis is a chronic inflammatory disease characterized by lipid accumulation and plaque formation in arterial vessel walls. Atherosclerotic plaques narrow the... (Review)
Review
Atherosclerosis is a chronic inflammatory disease characterized by lipid accumulation and plaque formation in arterial vessel walls. Atherosclerotic plaques narrow the arterial lumen to increase the risk of heart attacks, ischemic stroke and peripheral vascular disease, which are major and worldwide health and economic burdens. Macrophage accumulation within plaques is characteristic of all stages of atherosclerosis and their presence is a potential marker of disease activity and plaque stability. Macrophages engulf lipids and modified lipoproteins to form foam cells that express pro-inflammatory and chemotactic effector molecules, stress inducing factors and reactive oxygen species. They control plaque stability and rupture through secretion of metalloproteinases and extracellular matrix degradation. Although macrophages can worsen disease by propagating inflammation, they can stabilize atherosclerotic plaques through tissue remodeling, promoting the formation of a fibrous cap, clearing apoptotic cells to prevent necrotic core formation and through vascular repair. In atherosclerosis, macrophages respond to dyslipidaemia, cytokines, dying cells, metabolic factors, lipids, physical stimuli and epigenetic factors and exhibit heterogeneity in their activation depending on the stimuli they receive. Understanding these signals and the pathways driving macrophage function within developing and established plaques and how they can be pharmacologically modulated, represents a strategy for the prevention and treatment of atherosclerosis. This review focusses on the current understanding of factors controlling macrophage heterogeneity and function in atherosclerosis. Particular attention is given to the macrophage intracellular signaling pathways and transcription factors activated by biochemical and biophysical stimuli within plaques, and how they are integrated to regulate plaque formation and stability.
Topics: Humans; Macrophage Activation; Plaque, Atherosclerotic; Atherosclerosis; Signal Transduction; Lipoproteins
PubMed: 36416621
DOI: 10.1042/BST20220441 -
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 -
Immunologic Research Apr 2023Macro-autophagy is a highly conserved catabolic process among eukaryotes affecting macrophages. This work studies the genetic regulatory network involving the interplay...
Macro-autophagy is a highly conserved catabolic process among eukaryotes affecting macrophages. This work studies the genetic regulatory network involving the interplay between autophagy and macrophage polarization (activation). Autophagy-related genes (Atgs) and differentially expressed genes (DEGs) of macrophage polarization (M1-M2) were predicted, and their regulatory networks constructed. Naïve (M0) mouse bone marrow-derived monocytes were differentiated into M1 and M2a. Validation of the targets of Smad1, LC3A and LC3B, Atg16L1, Atg7, IL-6, CD68, Arg-1, and Vamp7 was performed in vitro. Immunophenotyping by flow cytometry revealed three macrophage phenotypes: M0 (IL-6 + /CD68 +), M1 (IL-6 + /CD68 + /Arg-1 +), and M2a (CD68 + /Arg-1). Confocal microscopy revealed increased autophagy in both M1 and M2a and a significant increase in the pre-autophagosomes size and number. Bafilomycin A increased the expression of CD68 and Arg-1 in all cell lineages. In conclusion, our approach predicted the protein targets mediating the interplay between autophagy and macrophage polarization. We suggest that autophagy reprograms macrophage polarization via CD68, arginase 1, Atg16L1-1, and Atg16L1-3. The current findings provide a foundation for the future use of macrophages in immunotherapy of different autoimmune disorders.
Topics: Animals; Mice; Autophagy; Gene Regulatory Networks; Interleukin-6; Macrophage Activation; Macrophages; Monocytes
PubMed: 36451006
DOI: 10.1007/s12026-022-09344-2 -
Cellular & Molecular Biology Letters Oct 2022Macrophages are influential members of the innate immune system that can be reversibly polarized by different microenvironment signals. Cell polarization leads to a wide... (Review)
Review
Macrophages are influential members of the innate immune system that can be reversibly polarized by different microenvironment signals. Cell polarization leads to a wide range of features, involving the migration, development, and organization of the cells. There is mounting evidence that macrophage polarization plays a key role in the initiation and development of a wide range of diseases. This study aims to give an overview of macrophage polarization, their different subtypes, and the importance of alternatively activated M2 macrophage and classically activated M1 macrophage in immune responses and pathological conditions. This review provides insight on the role of exosomes in M1/M2-like macrophage polarization and their potential as a promising therapeutic candidate.
Topics: Exosomes; Immunity; Immunomodulation; Macrophage Activation; Macrophages
PubMed: 36192691
DOI: 10.1186/s11658-022-00384-y -
Naunyn-Schmiedeberg's Archives of... Jan 2022Macrophages are myeloid immune cells, present in virtually all tissues which exhibit considerable functional plasticity and diversity. Macrophages are often subdivided... (Review)
Review
Macrophages are myeloid immune cells, present in virtually all tissues which exhibit considerable functional plasticity and diversity. Macrophages are often subdivided into two distinct subsets described as classically activated (M1) and alternatively activated (M2) macrophages. It has recently emerged that metabolites regulate the polarization and function of macrophages by altering metabolic pathways. These metabolites often cannot freely pass the cell membrane and are therefore transported by the corresponding metabolite transporters. Here, we reviewed how glucose, glutamate, lactate, fatty acid, and amino acid transporters are involved in the regulation of macrophage polarization. Understanding the interactions among metabolites, metabolite transporters, and macrophage function under physiological and pathological conditions may provide further insights for novel drug targets for the treatment of macrophage-associated diseases. In Brief Recent studies have shown that the polarization and function of macrophages are regulated by metabolites, most of which cannot pass freely through biofilms. Therefore, metabolite transporters required for the uptake of metabolites have emerged seen as important regulators of macrophage polarization and may represent novel drug targets for the treatment of macrophage-associated diseases. Here, we summarize the role of metabolite transporters as regulators of macrophage polarization.
Topics: Animals; Cell Membrane; Humans; Macrophage Activation; Macrophages; Membrane Transport Proteins
PubMed: 34851450
DOI: 10.1007/s00210-021-02173-4