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Clinica Chimica Acta; International... Feb 2020Atherosclerosis is a chronic inflammatory response that increases the risk of cardiovascular diseases. An in-depth study of the pathogenesis of atherosclerosis is... (Review)
Review
Atherosclerosis is a chronic inflammatory response that increases the risk of cardiovascular diseases. An in-depth study of the pathogenesis of atherosclerosis is critical for the treatment of atherosclerotic cardiovascular disease. The development of atherosclerosis involves many cells, such as endothelial cells, vascular smooth muscle cells, macrophages, and others. The considerable effects of macrophages in atherosclerosis are inextricably linked to macrophage polarization and the resulting phenotype. Moreover, the significant impact of macrophages on atherosclerosis depend not only on the function of the different macrophage phenotypes but also on the relative ratio of different phenotypes in the plaque. Research on atherosclerosis therapy indicates that the reduced plaque size and enhanced stability are partly due to modulating macrophage polarization. Therefore, regulating macrophage polarization and changing the proportion of macrophage phenotypes in plaques is a new therapeutic approach for atherosclerosis. This review provides a new perspective for atherosclerosis therapy by summarizing the relationship between macrophage polarization and atherosclerosis, as well as treatment targeting macrophage polarization.
Topics: Animals; Atherosclerosis; Humans; Macrophage Activation; Macrophages
PubMed: 31730809
DOI: 10.1016/j.cca.2019.10.034 -
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 -
Inflammation Aug 2022Lactate is a glycolytic product and a significant energy source. Moreover, it regulates gene transcription via lactylation of histones and non-histone proteins, i.e., a... (Review)
Review
Lactate is a glycolytic product and a significant energy source. Moreover, it regulates gene transcription via lactylation of histones and non-histone proteins, i.e., a novel posttranslational modification. This review summarizes recent advances related to lactylation in lactate metabolism and diseases. Notably, lactylation plays a vital role in cancer, inflammation, and regeneration; however, the specific mechanism remains unclear. Histone lactylation regulates oncogenic processes by targeting gene transcription and inflammation via macrophage activation. Eventually, we identified research gaps and recommended several primary directions for further studies.
Topics: Histones; Humans; Inflammation; Lactates; Macrophage Activation; Protein Processing, Post-Translational
PubMed: 35224683
DOI: 10.1007/s10753-022-01637-w -
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 -
Pharmacological Research May 2022Atherosclerosis is a chronic inflammatory disease and the pathological basis of many fatal cardiovascular diseases. Macrophages, the main inflammatory cells in... (Review)
Review
Atherosclerosis is a chronic inflammatory disease and the pathological basis of many fatal cardiovascular diseases. Macrophages, the main inflammatory cells in atherosclerotic plaque, have a paradox role in disease progression. In response to different microenvironments, macrophages mainly have two polarized directions: pro-inflammatory macrophages and anti-inflammatory macrophages. More and more evidence shows that macrophage is mechanosensitive and matrix stiffness regulate macrophage phenotypes in atherosclerosis. However, the molecular mechanism of matrix stiffness regulating macrophage polarization still lacks in-depth research, which hinders the development of new anti-atherosclerotic therapies. In this review, we discuss the important role of matrix stiffness in regulating macrophage polarization through mechanical signal transduction (Hippo, Piezo, cytoskeleton, and integrin) and epigenetic mechanisms (miRNA, DNA methylation, and histone). We hope to provide a new perspective for atherosclerosis therapy by targeting matrix stiffness and macrophage polarization.
Topics: Atherosclerosis; Humans; Macrophage Activation; Macrophages; MicroRNAs; Plaque, Atherosclerotic
PubMed: 35483516
DOI: 10.1016/j.phrs.2022.106236 -
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 -
Nature May 2023Inflammation is a complex physiological process triggered in response to harmful stimuli. It involves cells of the immune system capable of clearing sources of injury...
Inflammation is a complex physiological process triggered in response to harmful stimuli. It involves cells of the immune system capable of clearing sources of injury and damaged tissues. Excessive inflammation can occur as a result of infection and is a hallmark of several diseases. The molecular bases underlying inflammatory responses are not fully understood. Here we show that the cell surface glycoprotein CD44, which marks the acquisition of distinct cell phenotypes in the context of development, immunity and cancer progression, mediates the uptake of metals including copper. We identify a pool of chemically reactive copper(II) in mitochondria of inflammatory macrophages that catalyses NAD(H) redox cycling by activating hydrogen peroxide. Maintenance of NAD enables metabolic and epigenetic programming towards the inflammatory state. Targeting mitochondrial copper(II) with supformin (LCC-12), a rationally designed dimer of metformin, induces a reduction of the NAD(H) pool, leading to metabolic and epigenetic states that oppose macrophage activation. LCC-12 interferes with cell plasticity in other settings and reduces inflammation in mouse models of bacterial and viral infections. Our work highlights the central role of copper as a regulator of cell plasticity and unveils a therapeutic strategy based on metabolic reprogramming and the control of epigenetic cell states.
Topics: Animals; Mice; Copper; Inflammation; Macrophages; NAD; Signal Transduction; Mitochondria; Hydrogen Peroxide; Epigenesis, Genetic; Metformin; Oxidation-Reduction; Cell Plasticity; Macrophage Activation
PubMed: 37100912
DOI: 10.1038/s41586-023-06017-4 -
Gut Dec 2021As a canonical membrane tethering factor, the function of synbindin has been expanding and indicated in immune response. Here, we investigated the role of synbindin in...
OBJECTIVE
As a canonical membrane tethering factor, the function of synbindin has been expanding and indicated in immune response. Here, we investigated the role of synbindin in the regulation of toll-like receptor 4 (TLR4) signalling and macrophage response to microbiota during colitis.
DESIGN
Three distinct mouse models allowing global, myeloid-specific or intestinal epithelial cell-specific synbindin heterozygous deletion were constructed and applied to reveal the function of synbindin during dextran sodium sulfate (DSS) colitis. Effects of synbindin on TLR4 signalling and macrophage activation in response to bacterial lipopolysaccharide (LPS) or were evaluated. The colocalisation and interaction between synbindin and Rab7b were determined by immunofluorescence and coimmunoprecipitation. Synbindin expression in circulating monocytes and intestinal mucosal macrophages of patients with active IBD was detected.
RESULTS
Global synbindin haploinsufficiency greatly exacerbated DSS-induced intestinal inflammation. The increased susceptibility to DSS was abolished by gut microbiota depletion, while phenocopied by specific synbindin heterozygous deletion in myeloid cells rather than intestinal epithelial cells. Profoundly aberrant proinflammatory gene signatures and excessive TLR4 signalling were observed in macrophages with synbindin interference in response to bacterial LPS or . Synbindin was significantly increased in intestinal mucosal macrophages and circulating monocytes from both mice with DSS colitis and patients with active IBD. Interleukin 23 and granulocyte-macrophage colony-stimulating factor were identified to induce synbindin expression. Mechanistic characterisation indicated that synbindin colocalised and directly interacted with Rab7b, which coordinated the endosomal degradation pathway of TLR4 for signalling termination.
CONCLUSION
Synbindin was a key regulator of TLR4 signalling and restrained the proinflammatory macrophage activation against microbiota during colitis.
Topics: Animals; Colitis; Disease Models, Animal; Gastrointestinal Microbiome; Humans; Intestinal Mucosa; Macrophage Activation; Mice; Nerve Tissue Proteins; Signal Transduction; Toll-Like Receptor 4; Vesicular Transport Proteins; rab7 GTP-Binding Proteins
PubMed: 33441378
DOI: 10.1136/gutjnl-2020-321094 -
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