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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 -
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 -
Nature Immunology Jun 2018After activation, cells of the myeloid lineage undergo robust metabolic transitions, as well as discrete epigenetic changes, that can dictate both ongoing and future... (Review)
Review
After activation, cells of the myeloid lineage undergo robust metabolic transitions, as well as discrete epigenetic changes, that can dictate both ongoing and future inflammatory responses. In atherosclerosis, in which macrophages play central roles in the initiation, growth, and ultimately rupture of arterial plaques, altered metabolism is a key feature that dictates macrophage function and subsequent disease progression. This Review explores how factors central to the plaque microenvironment (for example, altered cholesterol metabolism, oxidative stress, hypoxia, apoptotic and necrotic cells, and hyperglycemia) shape the metabolic rewiring of macrophages in atherosclerosis as well as how these metabolic shifts in turn alter macrophage immune-effector and tissue-reparative functions. Finally, this overview offers insight into the challenges and opportunities of harnessing metabolism to modulate aberrant macrophage responses in disease.
Topics: Animals; Atherosclerosis; Humans; Macrophages
PubMed: 29777212
DOI: 10.1038/s41590-018-0113-3 -
Results and Problems in Cell... 2017Tissue macrophages are a heterogeneous cell population residing in all body tissues that contribute to the maintenance of homeostasis and trigger immune activation in... (Review)
Review
Tissue macrophages are a heterogeneous cell population residing in all body tissues that contribute to the maintenance of homeostasis and trigger immune activation in response to injurious stimuli. This heterogeneity may be associated with tissue-specific functions; however, the presence of distinct macrophage populations within the same microenvironment indicates that macrophage heterogeneity may also be influenced outside of tissue specialization. The F4/80 molecule was established as a unique marker of murine macrophages when a monoclonal antibody was found to recognize an antigen exclusively expressed by these cells. However, recent research has shown that F4/80 is expressed by other immune cells and is not equivalently expressed across tissue-specific macrophage lineages, including those residing in the same microenvironment, such as the peritoneum and spleen. In this context, two murine macrophage subtypes with distinct F4/80 expression patterns were recently found to coexist in the peritoneum, termed large peritoneal macrophages (LPMs) and small peritoneal macrophages (SPMs). However, the presence of phenotypic and functional heterogeneous macrophage subpopulations in the spleen was already known. Thus, although F4/80 surface expression continues to be the best method to identify tissue macrophages, additional molecules must also be examined to distinguish these cells from other immune cells.
Topics: Animals; Antigens, Differentiation; Biomarkers; Humans; Macrophages; Macrophages, Peritoneal; Mice; Peritoneum; Spleen
PubMed: 28455709
DOI: 10.1007/978-3-319-54090-0_7 -
Journal of Tissue Engineering and... Jan 2019Macrophages play a crucial role in regeneration and consecutive phases of wound healing. In this review, we summarise current knowledge on the ontogeny, origin,... (Review)
Review
Macrophages play a crucial role in regeneration and consecutive phases of wound healing. In this review, we summarise current knowledge on the ontogeny, origin, phenotypical heterogeneity, and functional exchangeability of macrophages participating in these processes. We also describe the genetic, pharmacologic, and bioengineering methods for manipulation of macrophage phenotype and functions and their potential for development of the novel, clinically applicable therapies.
Topics: Animals; Humans; Macrophages; Wound Healing
PubMed: 30445662
DOI: 10.1002/term.2772 -
Annual Review of Immunology 2015Macrophages are myeloid immune cells that are strategically positioned throughout the body tissues, where they ingest and degrade dead cells, debris, and foreign... (Review)
Review
Macrophages are myeloid immune cells that are strategically positioned throughout the body tissues, where they ingest and degrade dead cells, debris, and foreign material and orchestrate inflammatory processes. Here we review two major recent paradigm shifts in our understanding of tissue macrophage biology. The first is the realization that most tissue-resident macrophages are established prenatally and maintained through adulthood by longevity and self-renewal. Their generation and maintenance are thus independent from ongoing hematopoiesis, although the cells can be complemented by adult monocyte-derived macrophages. Second, aside from being immune sentinels, tissue macrophages form integral components of their host tissue. This entails their specialization in response to local environmental cues to contribute to the development and specific function of their tissue of residence. Factors that govern tissue macrophage specialization are emerging. Moreover, tissue specialization is reflected in discrete gene expression profiles of macrophages, as well as epigenetic signatures reporting actual and potential enhancer usage.
Topics: Animals; Cell Differentiation; Humans; Immunity; Macrophages; Organ Specificity; Phenotype
PubMed: 25861979
DOI: 10.1146/annurev-immunol-032414-112220 -
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 -
Journal For Immunotherapy of Cancer Jun 2021The peroxisome proliferator-activated receptor γ (PPAR-γ)-dependent upregulation of fatty acid oxidation (FAO) mediates protumor (also known as M2-like) polarization...
BACKGROUND
The peroxisome proliferator-activated receptor γ (PPAR-γ)-dependent upregulation of fatty acid oxidation (FAO) mediates protumor (also known as M2-like) polarization of tumor-associated macrophages (TAMs). However, upstream factors determining PPAR-γ upregulation in TAM protumor polarization are not fully identified. S100A4 plays crucial roles in promotion of cancer malignancy and mitochondrial metabolism. The fact that macrophage-derived S100A4 is major source of extracellular S100A4 suggests that macrophages contain a high abundance of intracellular S100A4. However, whether intracellular S100A4 in macrophages also contributes to cancer malignancy by enabling TAMs to acquire M2-like protumor activity remains unknown.
METHODS
Growth of tumor cells was evaluated in murine tumor models. TAMs were isolated from the tumor grafts in whole-body S100A4-knockout (KO), macrophage-specific S100A4-KO and transgenic S100A4 mice (expressing enhanced green fluorescent protein (EGFP) under the control of the S100A4 promoter). In vitro induction of macrophage M2 polarization was conducted by interleukin 4 (IL-4) stimulation. RNA-sequencing, real-time quantitative PCR, flow cytometry, western blotting, immunofluorescence staining and mass spectrometry were used to determine macrophage phenotype. Exogenous and endogenous FAO, FA uptake and measurement of lipid content were used to analyze macrophage metabolism.
RESULTS
TAMs contain two subsets based on whether they express S100A4 or not and that S100A4 subsets display protumor phenotypes. S100A4 can be induced by IL-4, an M2 activator of macrophage polarization. Mechanistically, S100A4 controls the upregulation of PPAR-γ, a transcription factor required for FAO induction during TAM protumor polarization. In S100A4 TAMs, PPAR-γ mainly upregulates CD36, a FA transporter, to enhance FA absorption as well as FAO. In contrast, S100A4-deficient TAMs exhibited decreased protumor activity because of failure in PPAR-γ upregulation-dependent FAO induction.
CONCLUSIONS
We find that macrophagic S100A4 enhances protumor macrophage polarization as a determinant of PPAR-γ-dependent FAO induction. Accordingly, our findings provide an insight into the general mechanisms of TAM polarization toward protumor phenotypes. Therefore, our results strongly suggest that targeting macrophagic S100A4 may be a potential strategy to prevent TAMs from re-differentiation toward a protumor phenotype.
Topics: Animals; Fatty Acids; Humans; Macrophages; Mice; Mice, Transgenic; PPAR gamma; S100 Calcium-Binding Protein A4; Signal Transduction; Tumor Microenvironment
PubMed: 34145030
DOI: 10.1136/jitc-2021-002548 -
Immunological Reviews Mar 2015By virtue of their position at the crossroads between the innate and adaptive immune response, macrophages play an essential role in the control of bacterial infections.... (Review)
Review
By virtue of their position at the crossroads between the innate and adaptive immune response, macrophages play an essential role in the control of bacterial infections. Paradoxically, macrophages serve as the natural habitat to Mycobacterium tuberculosis (Mtb). Mtb subverts the macrophage's mechanisms of intracellular killing and antigen presentation, leading ultimately to the development of tuberculosis (TB) disease. Here, we describe mechanisms of Mtb uptake by the macrophage and address key macrophage functions that are targeted by Mtb-specific effector molecules enabling this pathogen to circumvent host immune response. The macrophage functions described in this review include fusion between phagosomes and lysosomes, production of reactive oxygen and nitrogen species, antigen presentation and major histocompatibility complex class II expression and trafficking, as well as autophagy and apoptosis. All these are Mtb-targeted key cellular pathways, normally working in concert in the macrophage to recognize, respond, and activate 'proper' immune responses. We further analyze and discuss major molecular interactions between Mtb virulence factors and key macrophage proteins and provide implications for vaccine and drug development.
Topics: Animals; Antigen Presentation; Antigens, Bacterial; Apoptosis; Autophagy; Gene Expression Regulation; Histocompatibility Antigens Class II; Humans; Immune Evasion; Immune Tolerance; Immunity, Innate; Macrophages; Mycobacterium tuberculosis; NADPH Oxidases; Phagocytes; Phagocytosis; Protein Transport; Reactive Oxygen Species; Tuberculosis
PubMed: 25703562
DOI: 10.1111/imr.12268 -
Frontiers in Immunology 2023The physiological processes of cell growth, proliferation, differentiation, and apoptosis are closely related to STAT3, and it has been demonstrated that aberrant STAT3... (Review)
Review
The physiological processes of cell growth, proliferation, differentiation, and apoptosis are closely related to STAT3, and it has been demonstrated that aberrant STAT3 expression has an impact on the onset and progression of a number of inflammatory immunological disorders, fibrotic diseases, and malignancies. In order to produce the necessary biological effects, macrophages (M0) can be polarized into pro-inflammatory (M1) and anti-inflammatory (M2) types in response to various microenvironmental stimuli. STAT3 signaling is involved in macrophage polarization, and the research of the effect of STAT3 on macrophage polarization has gained attention in recent years. In order to provide references for the treatment and investigation of disorders related to macrophage polarization, this review compiles the pertinent signaling pathways associated with STAT3 and macrophage polarization from many fundamental studies.
Topics: Cell Differentiation; Macrophages; Signal Transduction; Inflammation; Humans; Animals
PubMed: 37081874
DOI: 10.3389/fimmu.2023.1160719