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Frontiers in Immunology 2021Macrophages can be polarized into classically activated macrophages (M1) and alternatively activated macrophages (M2) in the immune system, performing pro-inflammatory... (Comparative Study)
Comparative Study
Macrophages can be polarized into classically activated macrophages (M1) and alternatively activated macrophages (M2) in the immune system, performing pro-inflammatory and anti-inflammatory functions, respectively. Human THP-1 and mouse RAW264.7 cell line models have been widely used in various macrophage-associated studies, while the similarities and differences in protein expression profiles between the two macrophage models are still largely unclear. In this study, the protein expression profiles of M1 and M2 phenotypes from both THP-1 and RAW264.7 macrophages were systematically investigated using mass spectrometry-based proteomics. By quantitatively analyzing more than 5,000 proteins among different types of macrophages (M0, M1 and M2) from both cell lines, we identified a list of proteins that were uniquely up-regulated in each macrophage type and further confirmed 43 proteins that were commonly up-regulated in M1 macrophages of both cell lines. These results revealed considerable divergences of each polarization type between THP-1 and RAW264.7 macrophages. Moreover, the mRNA and protein expression of CMPK2, RSAD2, DDX58, and DHX58 were strongly up-regulated in M1 macrophages for both macrophage models. These data can serve as important resources for further studies of macrophage-associated diseases in experimental pathology using human and mouse cell line models.
Topics: Animals; Humans; Macrophage Activation; Macrophages; Mice; Proteomics; RAW 264.7 Cells; THP-1 Cells
PubMed: 34267761
DOI: 10.3389/fimmu.2021.700009 -
Mediators of Inflammation 2015The alternatively activated or M2 macrophages are immune cells with high phenotypic heterogeneity and are governing functions at the interface of immunity, tissue... (Review)
Review
The alternatively activated or M2 macrophages are immune cells with high phenotypic heterogeneity and are governing functions at the interface of immunity, tissue homeostasis, metabolism, and endocrine signaling. Today the M2 macrophages are identified based on the expression pattern of a set of M2 markers. These markers are transmembrane glycoproteins, scavenger receptors, enzymes, growth factors, hormones, cytokines, and cytokine receptors with diverse and often yet unexplored functions. This review discusses whether these M2 markers can be reliably used to identify M2 macrophages and define their functional subdivisions. Also, it provides an update on the novel signals of the tissue environment and the neuroendocrine system which shape the M2 activation. The possible evolutionary roots of the M2 macrophage functions are also discussed.
Topics: Humans; Macrophage Activation; Macrophages; Neurosecretory Systems
PubMed: 26089604
DOI: 10.1155/2015/816460 -
Frontiers in Immunology 2021Metformin is one of the most widely prescribed hypoglycemic drugs and has the potential to treat many diseases. More and more evidence shows that metformin can regulate... (Review)
Review
Metformin is one of the most widely prescribed hypoglycemic drugs and has the potential to treat many diseases. More and more evidence shows that metformin can regulate the function of macrophages in atherosclerosis, including reducing the differentiation of monocytes and inhibiting the inflammation, oxidative stress, polarization, foam cell formation and apoptosis of macrophages. The mechanisms by which metformin regulates the function of macrophages include AMPK, AMPK independent targets, NF-κB, ABCG5/8, Sirt1, FOXO1/FABP4 and HMGB1. On the basis of summarizing these studies, we further discussed the future research directions of metformin: single-cell RNA sequencing, neutrophil extracellular traps (NETs), epigenetic modification, and metformin-based combination drugs. In short, macrophages play an important role in a variety of diseases, and improving macrophage dysfunction may be an important mechanism for metformin to expand its pleiotropic pharmacological profile. In addition, the combination of metformin with other drugs that improve the function of macrophages (such as SGLT2 inhibitors, statins and IL-1β inhibitors/monoclonal antibodies) may further enhance the pleiotropic therapeutic potential of metformin in conditions such as atherosclerosis, obesity, cancer, dementia and aging.
Topics: Animals; Atherosclerosis; Biomarkers; Cardiometabolic Risk Factors; Cell Plasticity; Diabetes Complications; Diabetes Mellitus; Disease Susceptibility; Energy Metabolism; Humans; Macrophage Activation; Macrophages; Metformin; Signal Transduction
PubMed: 34163481
DOI: 10.3389/fimmu.2021.682853 -
Frontiers in Immunology 2021Persistent hyper-inflammation is a distinguishing pathophysiological characteristic of chronic wounds, and macrophage malfunction is considered as a major contributor... (Review)
Review
Persistent hyper-inflammation is a distinguishing pathophysiological characteristic of chronic wounds, and macrophage malfunction is considered as a major contributor thereof. In this review, we describe the origin and heterogeneity of macrophages during wound healing, and compare macrophage function in healing and non-healing wounds. We consider extrinsic and intrinsic factors driving wound macrophage dysregulation, and review systemic and topical therapeutic approaches for the restoration of macrophage response. Multidimensional analysis is highlighted through the integration of various high-throughput technologies, used to assess the diversity and activation states as well as cellular communication of macrophages in healing and non-healing wound. This research fills the gaps in current literature and provides the promising therapeutic interventions for chronic wounds.
Topics: Animals; Biomarkers; Chronic Disease; Humans; Inflammation; Macrophage Activation; Macrophages; Regeneration; Wound Healing
PubMed: 34220830
DOI: 10.3389/fimmu.2021.681710 -
Immunobiology Sep 2014Macrophages form a heterogeneous cell population displaying multiple functions, and can be polarized into pro- (M1) or anti-inflammatory (M2) macrophages, by...
Macrophages form a heterogeneous cell population displaying multiple functions, and can be polarized into pro- (M1) or anti-inflammatory (M2) macrophages, by environmental factors. Their activation status reflects a beneficial or detrimental role in various diseases. Currently several in vitro maturation and activation protocols are used to induce an M1 or M2 phenotype. Here, the impact of different maturation factors (NHS, M-CSF, or GM-CSF) and activation methods (IFN-γ/LPS, IL-4, dexamethason, IL-10) on the macrophage phenotype was determined. Regarding macrophage morphology, pro-inflammatory (M1) activation stimulated cell elongation, and anti-inflammatory (M2) activation induced a circular appearance. Activation with pro-inflammatory mediators led to increased CD40 and CD64 expression, whereas activation with anti-inflammatory factors resulted in increased levels of MR and CD163. Production of pro-inflammatory cytokines was induced by activation with IFN-γ/LPS, and TGF-β production was enhanced by the maturation factors M-CSF and GM-CSF. Our data demonstrate that macrophage marker expression and cytokine production in vitro is highly dependent on both maturation and activation methods. In vivo macrophage activation is far more complex, since a plethora of stimuli are present. Hence, defining the macrophage activation status ex vivo on a limited number of markers could be indecisive. From this study we conclude that maturation with M-CSF or GM-CSF induces a moderate anti- or pro-inflammatory state respectively, compared to maturation with NHS. CD40 and CD64 are the most distinctive makers for human M1 and CD163 and MR for M2 macrophage activation and therefore can be helpful in determining the activation status of human macrophages ex vivo.
Topics: Cell Differentiation; Cells, Cultured; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunologic Techniques; In Vitro Techniques; Macrophage Activation; Macrophage Colony-Stimulating Factor; Macrophages; Serum
PubMed: 24916404
DOI: 10.1016/j.imbio.2014.05.002 -
Nature Reviews. Immunology Sep 2018IFNγ is a cytokine with important roles in tissue homeostasis, immune and inflammatory responses and tumour immunosurveillance. Signalling by the IFNγ receptor... (Review)
Review
IFNγ is a cytokine with important roles in tissue homeostasis, immune and inflammatory responses and tumour immunosurveillance. Signalling by the IFNγ receptor activates the Janus kinase (JAK)-signal transducer and activator of transcription 1 (STAT1) pathway to induce the expression of classical interferon-stimulated genes that have key immune effector functions. This Review focuses on recent advances in our understanding of the transcriptional, chromatin-based and metabolic mechanisms that underlie IFNγ-mediated polarization of macrophages to an 'M1-like' state, which is characterized by increased pro-inflammatory activity and macrophage resistance to tolerogenic and anti-inflammatory factors. In addition, I describe the newly discovered effects of IFNγ on other leukocytes, vascular cells, adipose tissue cells, neurons and tumour cells that have important implications for autoimmunity, metabolic diseases, atherosclerosis, neurological diseases and immune checkpoint blockade cancer therapy.
Topics: Adaptive Immunity; Animals; Epigenesis, Genetic; Humans; Immune Tolerance; Immunotherapy; Inflammation; Interferon-gamma; Macrophage Activation; Macrophages; Metabolic Diseases; Models, Immunological; Neoplasms; Signal Transduction
PubMed: 29921905
DOI: 10.1038/s41577-018-0029-z -
Immunobiology Mar 2019In a diabetic milieu high levels of reactive oxygen species (ROS) are induced. This contributes to the vascular complications of diabetes. Recent studies have shown that... (Review)
Review
In a diabetic milieu high levels of reactive oxygen species (ROS) are induced. This contributes to the vascular complications of diabetes. Recent studies have shown that ROS formation is exacerbated in diabetic monocytes and macrophages due to a glycolytic metabolic shift. Macrophages are important players in the progression of diabetes and promote inflammation through the release of pro-inflammatory cytokines and proteases. Because ROS is an important mediator for the activation of pro-inflammatory signaling pathways, obesity and hyperglycemia-induced ROS production may favor induction of M1-like pro-inflammatory macrophages during diabetes onset and progression. ROS induces MAPK, STAT1, STAT6 and NFκB signaling, and interferes with macrophage differentiation via epigenetic (re)programming. Therefore, a comprehensive understanding of the impact of ROS on macrophage phenotype and function is needed in order to improve treatment of diabetes and its vascular complications. In the current comprehensive review, we dissect the role of ROS in macrophage polarization, and analyze how ROS production links metabolism and inflammation in diabetes and its complications. Finally, we discuss the contribution of ROS to the crosstalk between macrophages and endothelial cells in diabetic complications.
Topics: Animals; Diabetes Mellitus; Disease Susceptibility; Energy Metabolism; Humans; Immunomodulation; Macrophage Activation; Macrophages; Oxidative Stress; Reactive Oxygen Species; Signal Transduction
PubMed: 30739804
DOI: 10.1016/j.imbio.2018.11.010 -
Immunology and Cell Biology Mar 2019Macrophages are critically involved in wound healing, from dampening inflammation to clearing cell debris and coordinating tissue repair. Within the wound, the... (Review)
Review
Macrophages are critically involved in wound healing, from dampening inflammation to clearing cell debris and coordinating tissue repair. Within the wound, the complexity of macrophage function is increasingly recognized, with adverse outcomes when macrophages are inappropriately activated, such as in fibrosis or chronic non-healing wounds. Recent advances in in vivo and translational wound models, macrophage-specific deletions and new technologies to distinguish macrophage subsets, have uncovered the vast spectrum of macrophage activation and effector functions. Here, we summarize the main players in wound-healing macrophage activation and function, including cytokines, apoptotic cells, nucleotides and mechanical stimuli. We highlight recent studies demonstrating cooperation between these factors for optimal wound healing. Next, we describe recent technologies such as cell tracking and single-cell RNA-seq, which have uncovered remarkable plasticity and heterogeneity in blood-derived or tissue-resident macrophages and discuss the implications for wound healing. Lastly, we evaluate macrophage dysfunction in aberrant wound healing that occurs in aging, diabetes and fibrosis. A better understanding of the longevity and plasticity of wound-healing macrophages, and identification of unique macrophage subsets or specific effector molecules in wound healing, would shed light on the therapeutic potential of manipulating macrophage function for optimal wound healing.
Topics: Animals; Apoptosis; Biomarkers; Cell Plasticity; Cytokines; Disease Susceptibility; Fibrosis; Gene Expression Regulation; Humans; Inflammation Mediators; Macrophage Activation; Macrophages; Signal Transduction; Wound Healing
PubMed: 30746824
DOI: 10.1111/imcb.12236 -
Annual Review of Immunology Apr 2020A striking change has happened in the field of immunology whereby specific metabolic processes have been shown to be a critical determinant of immune cell activation.... (Review)
Review
A striking change has happened in the field of immunology whereby specific metabolic processes have been shown to be a critical determinant of immune cell activation. Multiple immune receptor types rewire metabolic pathways as a key part of how they promote effector functions. Perhaps surprisingly for immunologists, the Krebs cycle has emerged as the central immunometabolic hub of the macrophage. During proinflammatory macrophage activation, there is an accumulation of the Krebs cycle intermediates succinate and citrate, and the Krebs cycle-derived metabolite itaconate. These metabolites have distinct nonmetabolic signaling roles that influence inflammatory gene expression. A key bioenergetic target for the Krebs cycle, the electron transport chain, also becomes altered, generating reactive oxygen species from Complexes I and III. Similarly, alternatively activated macrophages require α-ketoglutarate-dependent epigenetic reprogramming to elicit anti-inflammatory gene expression. In this review, we discuss these advances and speculate on the possibility of targeting these events therapeutically for inflammatory diseases.
Topics: Animals; Citric Acid Cycle; Disease Susceptibility; Energy Metabolism; Humans; Immunity; Immunomodulation; Macrophage Activation; Macrophages; Signal Transduction
PubMed: 31986069
DOI: 10.1146/annurev-immunol-081619-104850 -
The Journal of Clinical Investigation Feb 2023The role of tumor-associated macrophages (TAMs), along with the regulatory mechanisms underlying distinct macrophage activation states, remains poorly understood in...
The role of tumor-associated macrophages (TAMs), along with the regulatory mechanisms underlying distinct macrophage activation states, remains poorly understood in prostate cancer (PCa). Herein, we report that PCa growth in mice with macrophage-specific Ubc9 deficiency is substantially suppressed compared with that in wild-type littermates, an effect partially ascribed to the augmented CD8+ T cell response. Biochemical and molecular analyses revealed that signal transducer and activator of transcription 4 (STAT4) is a crucial UBC9-mediated SUMOylation target, with lysine residue 350 (K350) as the major modification site. Site-directed mutation of STAT4 (K350R) enhanced its nuclear translocation and stability, thereby facilitating the proinflammatory activation of macrophages. Importantly, administration of the UBC9 inhibitor 2-D08 promoted the antitumor effect of TAMs and increased the expression of PD-1 on CD8+ T cells, supporting a synergistic antitumor efficacy once it combined with the immune checkpoint blockade therapy. Together, our results demonstrate that ablation of UBC9 could reverse the immunosuppressive phenotype of TAMs by promoting STAT4-mediated macrophage activation and macrophage-CD8+ T cell crosstalk, which provides valuable insights to halt the pathogenic process of tumorigenesis.
Topics: Animals; Humans; Male; Mice; CD8-Positive T-Lymphocytes; Macrophage Activation; Prostatic Neoplasms; Tumor Microenvironment
PubMed: 36626227
DOI: 10.1172/JCI158352