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JCI Insight Oct 2021Macrophage proinflammatory activation is an important etiologic component of the development of insulin resistance and metabolic dysfunction in obesity. However, the...
Macrophage proinflammatory activation is an important etiologic component of the development of insulin resistance and metabolic dysfunction in obesity. However, the underlying mechanisms are not clearly understood. Here, we demonstrate that a mitochondrial inner membrane protein, adenine nucleotide translocase 2 (ANT2), mediates proinflammatory activation of adipose tissue macrophages (ATMs) in obesity. Ant2 expression was increased in ATMs of obese mice compared with lean mice. Myeloid-specific ANT2-knockout (ANT2-MKO) mice showed decreased adipose tissue inflammation and improved insulin sensitivity and glucose tolerance in HFD/obesity. At the molecular level, we found that ANT2 mediates free fatty acid-induced mitochondrial permeability transition, leading to increased mitochondrial reactive oxygen species production and damage. In turn, this increased HIF-1α expression and NF-κB activation, leading to proinflammatory macrophage activation. Our results provide a previously unknown mechanism for how obesity induces proinflammatory activation of macrophages with propagation of low-grade chronic inflammation (metaflammation).
Topics: Adenine Nucleotide Translocator 2; Animals; Disease Models, Animal; Female; Humans; Inflammation; Macrophage Activation; Male; Mice; Obesity
PubMed: 34676827
DOI: 10.1172/jci.insight.147033 -
Proceedings of the National Academy of... Aug 2021Proinflammatory activation of macrophages in metabolic tissues is critically important in the induction of obesity-induced metaflammation. Here, we demonstrate that the...
Proinflammatory activation of macrophages in metabolic tissues is critically important in the induction of obesity-induced metaflammation. Here, we demonstrate that the soluble mannose receptor (sMR) plays a direct functional role in both macrophage activation and metaflammation. We show that sMR binds CD45 on macrophages and inhibits its phosphatase activity, leading to an Src/Akt/NF-κB-mediated cellular reprogramming toward an inflammatory phenotype both in vitro and in vivo. Remarkably, increased serum sMR levels were observed in obese mice and humans and directly correlated with body weight. Importantly, enhanced sMR levels increase serum proinflammatory cytokines, activate tissue macrophages, and promote insulin resistance. Altogether, our results reveal sMR as regulator of proinflammatory macrophage activation, which could constitute a therapeutic target for metaflammation and other hyperinflammatory diseases.
Topics: Animal Feed; Animals; Cells, Cultured; Cytokines; Diet, High-Fat; Gastrointestinal Microbiome; Gene Expression Regulation; Inflammation; Macrophage Activation; Macrophages; Male; Mannose Receptor; Membrane Proteins; Mice; Mice, Knockout; Random Allocation
PubMed: 34326259
DOI: 10.1073/pnas.2103304118 -
BioMed Research International 2016Atherosclerosis can be regarded as a chronic inflammatory state, in which macrophages play different and important roles. Phagocytic proinflammatory cells populate... (Review)
Review
Atherosclerosis can be regarded as a chronic inflammatory state, in which macrophages play different and important roles. Phagocytic proinflammatory cells populate growing atherosclerotic lesions, where they actively participate in cholesterol accumulation. Moreover, macrophages promote formation of complicated and unstable plaques by maintaining proinflammatory microenvironment. At the same time, anti-inflammatory macrophages contribute to tissue repair and remodelling and plaque stabilization. Macrophages therefore represent attractive targets for development of antiatherosclerotic therapy, which can aim to reduce monocyte recruitment to the lesion site, inhibit proinflammatory macrophages, or stimulate anti-inflammatory responses and cholesterol efflux. More studies are needed, however, to create a comprehensive classification of different macrophage phenotypes and to define their roles in the pathogenesis of atherosclerosis. In this review, we provide an overview of the current knowledge on macrophage diversity, activation, and plasticity in atherosclerosis and describe macrophage-based cellular tests for evaluation of potential antiatherosclerotic substances.
Topics: Animals; Atherosclerosis; Cytokines; Humans; Inflammasomes; Macrophage Activation; Macrophages; Models, Immunological; Transcriptome
PubMed: 27493969
DOI: 10.1155/2016/9582430 -
Biology Direct Sep 2023Tumor-associated macrophages (TAMs) are an important subset of innate immune cells in the tumor microenvironment, and they are pivotal regulators of tumor-promoting...
BACKGROUND
Tumor-associated macrophages (TAMs) are an important subset of innate immune cells in the tumor microenvironment, and they are pivotal regulators of tumor-promoting inflammation and tumor progression. Evidence has proven that TAM numbers are substantially increased in cancers, and most of these TAMs are polarized toward the alternatively activated M2 phenotype; Thus, these TAMs strongly promote the progression of cancer diseases. Type 1 innate lymphocytes (ILC1s) are present in high numbers in intestinal tissues and are characterized by the expression of the transcription factor T-bet and the secretion of interferon (IFN)-γ, which can promote macrophages to polarize toward the classically activated antitumor M1 phenotype. However, the relationship between these two cell subsets in colon cancer remains unclear.
METHODS
Flow cytometry was used to determine the percentages of M1-like macrophages, M2-like macrophages and ILC1s in colon cancer tissues and paracancerous healthy colon tissues in the AOM/DSS-induced mouse model of colon cancer. Furthermore, ILC1s were isolated and bone marrow-derived macrophages were generated to analyze the crosstalk that occurred between these cells when cocultured in vitro. Moreover, ILC1s were adoptively transferred or inhibited in vivo to explore the effects of ILC1s on tumor-infiltrating macrophages and tumor growth.
RESULTS
We found that the percentages of M1-like macrophages and ILC1s were decreased in colon cancer tissues, and these populations were positively correlated. ILC1s promoted the polarization of macrophages toward the classically activated M1-like phenotype in vitro, and this effect could be blocked by an anti-IFN-γ antibody. The in vivo results showed that the administration of the Group 1 innate lymphocyte-blocking anti-NK1.1 antibody decreased the number of M1-like macrophages in the tumor tissues of MC38 tumor-bearing mice and promoted tumor growth, and adoptive transfer of ILC1s inhibited tumors and increased the percentage of M1-like macrophages in MC38 tumor-bearing mice.
CONCLUSIONS
Our studies preliminarily prove for the first time that ILC1s promote the activation of M1-like macrophages by secreting IFN-γ and inhibit the progression of colon cancer, which may provide insight into immunotherapeutic approaches for colon cancer.
Topics: Animals; Mice; Macrophage Activation; Colonic Neoplasms; Interferon-gamma; Macrophages; Biological Transport; Tumor Microenvironment
PubMed: 37679802
DOI: 10.1186/s13062-023-00401-w -
International Journal of Molecular... Dec 2023The aim of this Special Issue is to investigate macrophages' high plasticity and ability to differentiate/polarize in response to numerous stimuli in the context of...
The aim of this Special Issue is to investigate macrophages' high plasticity and ability to differentiate/polarize in response to numerous stimuli in the context of diseases, infections, and biomolecules exposition (immunomodulators) [...].
Topics: Macrophages; Immunologic Factors; Macrophage Activation; Adjuvants, Immunologic
PubMed: 38139238
DOI: 10.3390/ijms242417409 -
Frontiers in Immunology 2019Inflammatory arthritis including rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) exhibit the shared feature of changes in activation and polarization... (Review)
Review
Inflammatory arthritis including rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) exhibit the shared feature of changes in activation and polarization of circulating monocytes and tissue macrophages. Numerous microRNAs (miRs) have been found to have key functions in regulating inflammation and macrophage polarization. Although there is increasing interest in the roles of miRs in both RA and JIA, less is known regarding how miRs relate to functional properties of immune cells, including monocytes and macrophages. Interestingly, miRs can function both to promote inflammatory phenotypes and pro-inflammatory polarization, as well as through negative-feedback loops to limit inflammation. Here, we review the functional roles of several miRs in macrophages in inflammatory arthritis, with a particular focus on vivo effects of miR alteration in experimental arthritis. We also consider how current efforts to target miRs clinically could modify functional monocyte and macrophage polarization , and serve as novel therapies for diseases such as RA and JIA.
Topics: Animals; Arthritis, Experimental; Arthritis, Juvenile; Arthritis, Rheumatoid; Gene Expression Regulation; Humans; Macrophage Activation; Macrophages; MicroRNAs; Phenotype
PubMed: 31572403
DOI: 10.3389/fimmu.2019.02217 -
Frontiers in Endocrinology 2020Type-2 diabetes (T2D) is a disease of two etiologies: metabolic and inflammatory. At the cross-section of these etiologies lays the phenomenon of metabolic inflammation.... (Review)
Review
Type-2 diabetes (T2D) is a disease of two etiologies: metabolic and inflammatory. At the cross-section of these etiologies lays the phenomenon of metabolic inflammation. Whilst metabolic inflammation is characterized as systemic, a common starting point is the tissue-resident macrophage, who's successful physiological or aberrant pathological adaptation to its microenvironment determines disease course and severity. This review will highlight the key mechanisms in macrophage polarization, inflammatory and non-inflammatory signaling that dictates the development and progression of insulin resistance and T2D. We first describe the known homeostatic functions of tissue macrophages in insulin secreting and major insulin sensitive tissues. Importantly we highlight the known mechanisms of aberrant macrophage activation in these tissues and the ways in which this leads to impairment of insulin sensitivity/secretion and the development of T2D. We next describe the cellular mechanisms that are known to dictate macrophage polarization. We review recent progress in macrophage bio-energetics, an emerging field of research that places cellular metabolism at the center of immune-effector function. Importantly, following the advent of the metabolically-activated macrophage, we cover the known transcriptional and epigenetic factors that canonically and non-canonically dictate macrophage differentiation and inflammatory polarization. In closing perspectives, we discuss emerging research themes and highlight novel non-inflammatory or non-immune roles that tissue macrophages have in maintaining microenvironmental and systemic homeostasis.
Topics: Animals; Diabetes Mellitus, Type 2; Homeostasis; Humans; Insulin; Insulin Resistance; Macrophage Activation; Signal Transduction
PubMed: 32140136
DOI: 10.3389/fendo.2020.00062 -
Frontiers in Immunology 2024Macrophages are crucial cells in the human body's innate immunity and are engaged in a variety of non-inflammatory reactions. Macrophages can develop into two kinds when... (Review)
Review
Macrophages are crucial cells in the human body's innate immunity and are engaged in a variety of non-inflammatory reactions. Macrophages can develop into two kinds when stimulated by distinct internal environments: pro-inflammatory M1-like macrophages and anti-inflammatory M2-type macrophages. During inflammation, the two kinds of macrophages are activated alternatively, and maintaining a reasonably steady ratio is critical for maintaining homeostasis . M1 macrophages can induce inflammation, but M2 macrophages suppress it. The imbalance between the two kinds of macrophages will have a significant impact on the illness process. As a result, there are an increasing number of research being conducted on relieving or curing illnesses by altering the amount of macrophages. This review summarizes the role of macrophage polarization in various inflammatory diseases, including autoimmune diseases (RA, EAE, MS, AIH, IBD, CD), allergic diseases (allergic rhinitis, allergic dermatitis, allergic asthma), atherosclerosis, obesity and type 2 diabetes, metabolic homeostasis, and the compounds or drugs that have been discovered or applied to the treatment of these diseases by targeting macrophage polarization.
Topics: Humans; Macrophages; Inflammation; Animals; Macrophage Activation; Hypersensitivity; Autoimmune Diseases
PubMed: 38660308
DOI: 10.3389/fimmu.2024.1352946 -
BMB Reports Nov 2022Macrophage activation has long been implicated in a myriad of human pathophysiology, particularly in the context of the dysregulated capacities of an unleashing... (Review)
Review
Macrophage activation has long been implicated in a myriad of human pathophysiology, particularly in the context of the dysregulated capacities of an unleashing intracellular or/and extracellular inflammatory response. A growing number of studies have functionally coupled the macrophages' inflammatory capacities with dynamic metabolic reprogramming which occurs during activation, albeit the results have been mostly interpreted through classic metabolism point of view; macrophages take advantage of the rewired metabolism as a source of energy and for biosynthetic precursors. However, a specific subset of metabolic products, namely immune-modulatory metabolites, has recently emerged as significant regulatory signals which control inflammatory responses in macrophages and the relevant extracellular milieu. In this review, we introduce recently highlighted immuno-modulatory metabolites, with the aim of understanding their physiological and pathological relevance in the macrophage inflammatory response. [BMB Reports 2022; 55(11): 519-527].
Topics: Humans; Macrophage Activation; Macrophages; Immunomodulation; Inflammation
PubMed: 36195564
DOI: 10.5483/BMBRep.2022.55.11.128 -
Mediators of Inflammation 2018Monocyte and macrophage diversity is evidenced by the modulation of cell surface markers and differential production of soluble mediators. These immune cells play key... (Review)
Review
Monocyte and macrophage diversity is evidenced by the modulation of cell surface markers and differential production of soluble mediators. These immune cells play key roles in controlling tissue homeostasis, infections, and excessive inflammation. Macrophages remove dead cells in a process named efferocytosis, contributing to the healthy tissue maintenance. Recently, it became clear that the main macrophage functions are under metabolic control. Modulation of glucose, fatty acid, and amino acid metabolism is associated with various macrophage activations in response to external stimuli. Deciphering these metabolic pathways provided critical information about macrophage functions.
Topics: Amino Acids; Animals; Fatty Acids; Glucose; Humans; Macrophage Activation; Macrophages; Phagocytosis
PubMed: 30647530
DOI: 10.1155/2018/2426138