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Immunity Jan 2023Metazoan tissue specification is associated with integration of macrophage lineage cells in sub-tissular niches to promote tissue development and homeostasis. Oncogenic... (Review)
Review
Metazoan tissue specification is associated with integration of macrophage lineage cells in sub-tissular niches to promote tissue development and homeostasis. Oncogenic transformation, most prevalently of epithelial cell lineages, results in maladaptation of resident tissue macrophage differentiation pathways to generate parenchymal and interstitial tumor-associated macrophages that largely foster cancer progression. In addition to growth factors, nutrients that can be consumed, stored, recycled, or converted to signaling molecules have emerged as crucial regulators of macrophage responses in tumor. Here, we review how nutrient acquisition through plasma membrane transporters and engulfment pathways control tumor-associated macrophage differentiation and function. We also discuss how nutrient metabolism regulates tumor-associated macrophages and how these processes may be targeted for cancer therapy.
Topics: Animals; Humans; Tumor-Associated Macrophages; Macrophages; Cell Differentiation; Neoplasms; Nutrients
PubMed: 36630912
DOI: 10.1016/j.immuni.2022.12.003 -
Frontiers in Immunology 2020The immunosuppressive status of the tumor microenvironment (TME) remains poorly defined due to a lack of understanding regarding the function of tumor-associated... (Review)
Review
The immunosuppressive status of the tumor microenvironment (TME) remains poorly defined due to a lack of understanding regarding the function of tumor-associated macrophages (TAMs), which are abundant in the TME. TAMs are crucial drivers of tumor progression, metastasis, and resistance to therapy. Intra- and inter-tumoral spatial heterogeneities are potential keys to understanding the relationships between subpopulations of TAMs and their functions. Antitumor M1-like and pro-tumor M2-like TAMs coexist within tumors, and the opposing effects of these M1/M2 subpopulations on tumors directly impact current strategies to improve antitumor immune responses. Recent studies have found significant differences among monocytes or macrophages from distinct tumors, and other investigations have explored the existence of diverse TAM subsets at the molecular level. In this review, we discuss emerging evidence highlighting the redefinition of TAM subpopulations and functions in the TME and the possibility of separating macrophage subsets with distinct functions into antitumor M1-like and pro-tumor M2-like TAMs during the development of tumors. Such redefinition may relate to the differential cellular origin and monocyte and macrophage plasticity or heterogeneity of TAMs, which all potentially impact macrophage biomarkers and our understanding of how the phenotypes of TAMs are dictated by their ontogeny, activation status, and localization. Therefore, the detailed landscape of TAMs must be deciphered with the integration of new technologies, such as multiplexed immunohistochemistry (mIHC), mass cytometry by time-of-flight (CyTOF), single-cell RNA-seq (scRNA-seq), spatial transcriptomics, and systems biology approaches, for analyses of the TME.
Topics: Animals; Cell Plasticity; Gene Expression Regulation, Neoplastic; Humans; Macrophages; Neoplasms; Phenotype; Signal Transduction; Transcriptome; Tumor Microenvironment
PubMed: 32849616
DOI: 10.3389/fimmu.2020.01731 -
Pharmacology & Therapeutics Nov 2022As the first line of defence in the lung, alveolar macrophage contributes to maintaining lung immune homoeostasis. Characterized by the heterogeneity and plasticity,... (Review)
Review
As the first line of defence in the lung, alveolar macrophage contributes to maintaining lung immune homoeostasis. Characterized by the heterogeneity and plasticity, macrophages polarize into two pro-inflammatory and anti-inflammatory phenotypes regarding the biological and pathological environment. In the past decade, numerous studies have revolutionized the relationship between cellular metabolism and macrophage functions. Mitochondria dysfunctions, which results in altered cellular metabolic profile, were observed in the alveolar macrophages during chronic lung diseases. In addition, alveolar macrophages adapt metabolic reprogramming to produce an immune response against the pathogens. Here, we outline the role of mitochondria in the development of macrophage phenotypes and functions and highlight the mitochondrial dysfunction in the setting of chronic lung diseases. Lastly, we emphasize the therapeutic relevance of targeting metabolic pathways in alveolar macrophages, which may shed light on developing novel strategies against chronic lung diseases.
Topics: Humans; Macrophages; Lung Diseases; Macrophages, Alveolar; Mitochondria; Lung
PubMed: 35569553
DOI: 10.1016/j.pharmthera.2022.108208 -
Frontiers in Cellular and Infection... 2023(Mtb), the causative agent of Tuberculosis (TB), remains a pathogen of great interest on a global scale. This airborne pathogen affects the lungs, where it interacts... (Review)
Review
(Mtb), the causative agent of Tuberculosis (TB), remains a pathogen of great interest on a global scale. This airborne pathogen affects the lungs, where it interacts with macrophages. Acidic pH, oxidative and nitrosative stressors, and food restrictions make the macrophage's internal milieu unfriendly to foreign bodies. Mtb subverts the host immune system and causes infection due to its genetic arsenal and secreted effector proteins. and research have examined Mtb-host macrophage interaction. This interaction is a crucial stage in Mtb infection because lung macrophages are the first immune cells Mtb encounters in the host. This review summarizes Mtb effectors that interact with macrophages. It also examines how macrophages control and eliminate Mtb and how Mtb manipulates macrophage defense mechanisms for its own survival. Understanding these mechanisms is crucial for TB prevention, diagnosis, and treatment.
Topics: Humans; Mycobacterium tuberculosis; Macrophages; Tuberculosis; Macrophages, Alveolar; Lung; Host-Pathogen Interactions
PubMed: 36936766
DOI: 10.3389/fcimb.2023.1062963 -
Cancer Research Mar 2021Adoptive cell therapy with genetically modified T cells has generated exciting outcomes in hematologic malignancies, but its application to solid tumors has proven... (Review)
Review
Adoptive cell therapy with genetically modified T cells has generated exciting outcomes in hematologic malignancies, but its application to solid tumors has proven challenging. This gap has spurred the investigation of alternative immune cells as therapeutics. Macrophages are potent immune effector cells whose functional plasticity leads to antitumor as well as protumor function in different settings, and this plasticity has led to notable efforts to deplete or repolarize tumor-associated macrophages. Alternatively, macrophages could be adoptively transferred after genetic modification. In this review, we highlight the role of macrophages in solid tumors, the progress made with macrophage-focused immunotherapeutic modalities, and the emergence of chimeric antigen receptor macrophage cell therapy.
Topics: Animals; Cell- and Tissue-Based Therapy; Humans; Immunotherapy; Immunotherapy, Adoptive; Macrophages; Neoplasms; Tumor-Associated Macrophages
PubMed: 33203697
DOI: 10.1158/0008-5472.CAN-20-2990 -
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 -
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 -
Journal of Immunological Methods Dec 2022Macrophages are scavenger cells and a fundamental part of innate and adaptive immune responses, and they are important in wound repair and tissue remodeling. The...
Macrophages are scavenger cells and a fundamental part of innate and adaptive immune responses, and they are important in wound repair and tissue remodeling. The functions of macrophages include engulfing and killing invading pathogens, processing and presenting antigens, initiation of inflammation, secreting cytokines and other inflammatory mediators, and participating in the maintenance and repair of tissues. Based on functional differences and surface and intracellular marker expression, macrophages can be generally divided into either M1 (inflammatory) or M2 (wound healing); the M2 type can be further divided into M2a, M2b, M2c, and M2d. However, due to the time, effort, and cost of establishing a panel of markers that could thoroughly assess polarization, the characterization of types and subtypes is usually done using three markers or fewer. This can lead to problems, because the expression of some of the most widely used polarization markers can be altered by commonly used inflammatory or immunological stimuli. We have developed and optimized an eleven-color polychromatic flow cytometric assay for macrophage subtype identification that prevents mischaracterization due to stimulus-induced changes in individual markers by using partially redundant markers for which at least one is not substantially affected by a commonly used inflammatory stimulus (LPS). We polarized 3 × 10 RAW 264.7 cells, a mouse macrophage cell line, with IFN-γ (± LPS), IL-4 or IL-10 to derive M1, M2a, or M2c macrophage subtypes, respectively. The TNF-α concentration in cell supernatants was tested by ELISA to verify polarization. Then polarized cells were labeled with the following antibodies and assessed by flow cytometry to identify marker expression: F4/80, Arginase 1, TLR4, CD86, VEGF, CD14, CD206, MHC Class II, and TNF-α (surface and internal). Here we have identified clear distinctions between macrophage subtypes using these markers, and we anticipate that this panel will help disclose more details of the macrophage's role in the immune response and will save investigators the time and cost usually required to identify appropriate antibodies that do not interfere with each other or lead to difficult color compensation issues.
Topics: Animals; Mice; Flow Cytometry; Tumor Necrosis Factor-alpha; Macrophages
PubMed: 36265578
DOI: 10.1016/j.jim.2022.113378