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Journal of Experimental & Clinical... Jul 2018Treatment strategies targeting tumor-associated macrophages (TAMs) have been proposed in cancer areas. The functional alterations of macrophages in the microenvironment...
BACKGROUND
Treatment strategies targeting tumor-associated macrophages (TAMs) have been proposed in cancer areas. The functional alterations of macrophages in the microenvironment during the tumorigenesis of human epithelial cancer remain poorly understood. Here, we explored phenotypic alteration of macrophages during the development of oral squamous cell carcinoma (OSCC).
METHODS
Conditioned media (CM) and exosome supernatants were harvested from normal oral epithelium, oral leukoplakia cells and OSCC cells. We measured phenotypic alteration of macrophages using flow cytometry, luminex assays, and quantitative real-time PCR assay. Intracellular signaling pathway analysis, mass spectrometry proteomics, western blotting, enzyme-linked immunosorbent assay, immunohistochemical staining, and bioinformatics analysis were performed to uncover the underlying mechanisms.
RESULTS
THP-1-derived and PBMCs derived macrophages exhibited an M1-like phenotype but not M2-like phenotype, when treated with CM from OSCC cells but not with the CM from normal epithelium or leukoplakia cells. Further investigations revealed that macrophages were activated by taking up exosomes released from OSCC cells through p38, Akt, and SAPK/JNK signaling at the early phase. We further provided evidences that THBS1 derived from OSCC exosomes participated in the polarization of macrophages to an M1-like phenotype. Reciprocally, CM from exosomes induced M1-like TAMs and significantly promoted migration of OSCC cells.
CONCLUSIONS
We proposed a novel paracrine loop between cancer cells and macrophages based on exosomes from OSCC. Therefore, target management of M1-like TAMs polarized by exosomes shows great potential as a therapeutic target for the control of cancerous migration in OSCC.
Topics: Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Movement; Cell Proliferation; Culture Media, Conditioned; Exosomes; Humans; Immunohistochemistry; MAP Kinase Signaling System; Macrophage Activation; Macrophages; Molecular Imaging; Mouth Neoplasms; Thrombospondin 1; Tumor Microenvironment
PubMed: 29986759
DOI: 10.1186/s13046-018-0815-2 -
Results and Problems in Cell... 2017Macrophages constitute a heterogeneous population of myeloid cells that are essential for maintaining homeostasis and as a first line of innate responders controlling... (Review)
Review
Macrophages constitute a heterogeneous population of myeloid cells that are essential for maintaining homeostasis and as a first line of innate responders controlling and organizing host defenses against pathogens. Monocyte-macrophage lineage cells are among the most functionally diverse and plastic cells of the immune system. They undergo specific activation into functionally distinct phenotypes in response to immune signals and microbial products. In mammals, macrophage functional heterogeneity is defined by two activation states, M1 and M2, which represent two polar ends of a continuum exhibiting pro-inflammatory and tissue repair activities, respectively. While the ancient evolutionary origin of macrophages as phagocytic defenders is well established, the evolutionary roots of the specialized division of macrophages into subsets with polarized activation phenotypes is less well defined. Accordingly, this chapter focuses on recent advances in the understanding of the evolution of macrophage polarization and functional heterogeneity with a focus on ectothermic vertebrates.
Topics: Animals; Cell Lineage; Humans; Macrophage Activation; Macrophages
PubMed: 28455703
DOI: 10.1007/978-3-319-54090-0_1 -
Journal of Immunology Research 2020Atherosclerosis (AS), a typical chronic inflammatory vascular disease, is the main pathological basis of ischemic cardio/cerebrovascular disease (CVD). Long-term... (Review)
Review
Atherosclerosis (AS), a typical chronic inflammatory vascular disease, is the main pathological basis of ischemic cardio/cerebrovascular disease (CVD). Long-term administration was characterized with low efficacy and serious side effects, while the macrophages with attractive intrinsic homing target have great potential in the efficient and safe management of AS. In this review, we focused on the systematical summary of the macrophage-based therapies in AS management, including macrophage autophagy, polarization, targeted delivery, microenvironment-triggered drug release, and macrophage- or macrophage membrane-based drug carrier. In conclusion, macrophage-based therapies have great promise to effectively manage AS in future research and clinic translation.
Topics: Animals; Atherosclerosis; Autophagy; Cardiovascular Agents; Cell Membrane; Disease Models, Animal; Drug Carriers; Humans; Inflammasomes; Macrophage Activation; Macrophages
PubMed: 32411803
DOI: 10.1155/2020/8131754 -
Mucosal Immunology Dec 2023Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are serious health problems that manifest as acute respiratory failure in response to different...
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are serious health problems that manifest as acute respiratory failure in response to different conditions, including viral respiratory infections. Recently, the inhibitory properties of leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) were demonstrated in allergic and viral airway inflammation. In this study, we investigate the implication of LAIR-1 in ALI/ARDS and explore the underlying mechanisms. Polyinosinic:polycytidylic acid, a synthetic analog of double-stranded RNA, was used to mimic acute inflammation in viral infections. We demonstrate that LAIR-1 is predominantly expressed on macrophages and regulates their recruitment to the lungs as well as their activation in response to polyinosinic:polycytidylic acid. Interestingly, LAIR-1 deficiency increases neutrophil recruitment as well as lung resistance and permeability. In particular, we highlight the capacity of LAIR-1 to regulate the secretion of CXCL10, considered a key marker of macrophage overactivation in acute lung inflammation. We also reveal in COVID-19-induced lung inflammation that LAIR1 is upregulated on lung macrophages in correlation with relevant immune regulatory genes. Altogether, our findings demonstrate the implication of LAIR-1 in the pathogenesis of ALI/ARDS by means of the regulation of macrophages, thereby providing the basis of a novel therapeutic target.
Topics: Humans; Macrophage Activation; Acute Lung Injury; Lung; Pneumonia; Inflammation; Respiratory Distress Syndrome; Poly C
PubMed: 37634572
DOI: 10.1016/j.mucimm.2023.08.003 -
Frontiers in Immunology 2018Overcrowding conditions and temperatures shifts regularly manifest in large-scale infections of farmed fish, resulting in economic losses for the global aquaculture... (Review)
Review
Overcrowding conditions and temperatures shifts regularly manifest in large-scale infections of farmed fish, resulting in economic losses for the global aquaculture industries. Increased understanding of the functional mechanisms of fish antimicrobial host defenses is an important step forward in prevention of pathogen-induced morbidity and mortality in aquaculture setting. Like other vertebrates, macrophage-lineage cells are integral to fish immune responses and for this reason, much of the recent fish immunology research has focused on fish macrophage biology. These studies have revealed notable similarities as well as striking differences in the molecular strategies by which fish and higher vertebrates control their respective macrophage polarization and functionality. In this review, we address the current understanding of the biological mechanisms of teleost macrophage functional heterogeneity and immunity, focusing on the key cytokine regulators that control fish macrophage development and their antimicrobial armamentarium.
Topics: Adaptive Immunity; Animals; Biomarkers; Disease Resistance; Fishes; Gene Expression Regulation; Host-Pathogen Interactions; Immunity; Immunity, Innate; Macrophage Activation; Macrophages; Signal Transduction
PubMed: 29892285
DOI: 10.3389/fimmu.2018.01105 -
Seminars in Immunology Oct 2016Macrophages are heterogeneous cells that play a key role in inflammatory and tissue reparative responses. Over the past decade it has become clear that shifts in... (Review)
Review
Macrophages are heterogeneous cells that play a key role in inflammatory and tissue reparative responses. Over the past decade it has become clear that shifts in cellular metabolism are important determinants of macrophage function and phenotype. At the same time, our appreciation of macrophage diversity in vivo has also been increasing. Factors such as cell origin and tissue localization are now recognized as important variables that influence macrophage biology. Whether different macrophage populations also have unique metabolic phenotypes has not been extensively explored. In this article, we will discuss the importance of understanding how macrophage origin can modulate metabolic programming and influence inflammatory responses.
Topics: Animals; Energy Metabolism; Gene Expression Regulation; Humans; Immunomodulation; Macrophage Activation; Macrophages; Metabolic Networks and Pathways; Organ Specificity; Phenotype
PubMed: 27771140
DOI: 10.1016/j.smim.2016.10.004 -
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 -
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 -
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