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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 -
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 -
Frontiers in Immunology 2021Cellular associations in the bone microenvironment are involved in modulating the balance between bone remodeling and resorption, which is necessary for maintaining a... (Review)
Review
Cellular associations in the bone microenvironment are involved in modulating the balance between bone remodeling and resorption, which is necessary for maintaining a normal bone morphology. Macrophages and osteoclasts are both vital components of the bone marrow. Macrophages can interact with osteoclasts and regulate bone metabolism by secreting a variety of cytokines, which make a significant contribution to the associations. Although, recent studies have fully explored either macrophages or osteoclasts, indicating the significance of these two types of cells. However, it is of high importance to report the latest discoveries on the relationships between these two myeloid-derived cells in the field of osteoimmunology. Therefore, this paper reviews this topic from three novel aspects of the origin, polarization, and subgroups based on the previous work, to provide a reference for future research and treatment of bone-related diseases.
Topics: Animals; Cell Communication; Cell Polarity; Cytokines; Humans; Macrophages; Nitric Oxide; Osteoclasts; Reactive Oxygen Species; Tumor-Associated Macrophages
PubMed: 34925351
DOI: 10.3389/fimmu.2021.778078 -
Frontiers in Immunology 2021Osteoimmunity is involved in regulating the balance of bone remodeling and resorption, and is essential for maintaining normal bone morphology. The interaction between... (Review)
Review
Osteoimmunity is involved in regulating the balance of bone remodeling and resorption, and is essential for maintaining normal bone morphology. The interaction between immune cells and osteoclasts in the bone marrow or joint cavity is the basis of osteoimmunity, in which the macrophage-osteoclast axis plays a vital role. Monocytes or tissue-specific macrophages (macrophages resident in tissues) are an important origin of osteoclasts in inflammatory and immune environment. Although there are many reports on macrophages and osteoclasts, there is still a lack of systematic reviews on the macrophage-osteoclast axis in osteoimmunity. Elucidating the role of the macrophage-osteoclast axis in osteoimmunity is of great significance for the research or treatment of bone damage caused by inflammation and immune diseases. In this article, we introduced in detail the concept of osteoimmunity and the mechanism and regulators of the differentiation of macrophages into osteoclasts. Furthermore, we described the role of the macrophage-osteoclast axis in typical bone damage caused by inflammation and immune diseases. These provide a clear knowledge framework for studying macrophages and osteoclasts in inflammatory and immune environments. And targeting the macrophage-osteoclast axis may be an effective strategy to treat bone damage caused by inflammation and immune diseases.
Topics: Animals; Arthritis, Rheumatoid; Bone Remodeling; Bone Resorption; Bone and Bones; Cell Differentiation; Humans; Macrophages; Osteoclasts
PubMed: 33868316
DOI: 10.3389/fimmu.2021.664871 -
Laboratory Investigation; a Journal of... Feb 2020Transient receptor ion channels have emerged as immensely important channels/receptors in diverse physiological and pathological responses. Of particular interest is the... (Review)
Review
Transient receptor ion channels have emerged as immensely important channels/receptors in diverse physiological and pathological responses. Of particular interest is the transient receptor potential channel subfamily V member 4 (TRPV4), which is a polymodal, nonselective, calcium-permeant cation channel, and is activated by both endogenous and exogenous stimuli. Both neuronal and nonneuronal cells express functional TRPV4, which is responsive to a variety of biochemical and biomechanical stimuli. Emerging discoveries have advanced our understanding of the role of macrophage TRPV4 in numerous inflammatory diseases. In lung injury, TRPV4 mediates macrophage phagocytosis, secretion of pro-resolution cytokines, and generation of reactive oxygen species. TRPV4 regulates lipid-laden macrophage foam cell formation, the hallmark of atheroinflammatory conditions, in response to matrix stiffness and lipopolysaccharide stimulation. Accumulating data also point to a role of macrophage TRPV4 in the pathogenesis of the foreign body response, a chronic inflammatory condition, through the formation of foreign body giant cells. Deletion of TRPV4 in macrophages suppresses the allergic and nonallergic itch in a mouse model, suggesting a role of TRPV4 in skin disease. Here, we discuss the current understanding of the role of macrophage TRPV4 in various inflammatory conditions.
Topics: Animals; Atherosclerosis; Fibrosis; Humans; Inflammation; Lung Diseases; Macrophages; Mice; Pruritus; TRPV Cation Channels
PubMed: 31645630
DOI: 10.1038/s41374-019-0334-6 -
Frontiers in Immunology 2022() is the causative agent of human tuberculosis (TB) which primarily infects the macrophages. Nearly a quarter of the world's population is infected latently by . Only... (Review)
Review
() is the causative agent of human tuberculosis (TB) which primarily infects the macrophages. Nearly a quarter of the world's population is infected latently by . Only around 5%-10% of those infected develop active TB disease, particularly during suppressed host immune conditions or comorbidity such as HIV, hinting toward the heterogeneity of infection. The aerosolized first reaches the lungs, and the resident alveolar macrophages (AMs) are among the first cells to encounter the infection. Evidence suggests that early clearance of infection is associated with robust innate immune responses in resident macrophages. In addition to lung-resident macrophage subsets, the recruited monocytes and monocyte-derived macrophages (MDMs) have been suggested to have a protective role during infection. , by virtue of its unique cell surface lipids and secreted protein effectors, can evade killing by the innate immune cells and preferentially establish a niche within the AMs. Continuous efforts to delineate the determinants of host defense mechanisms have brought to the center stage the crucial role of macrophage phenotypical variations for functional adaptations in TB. The morphological and functional heterogeneity and plasticity of the macrophages aid in confining the dissemination of However, during a suppressed or hyperactivated immune state, the virulence factors can affect macrophage homeostasis which may skew to favor pathogen growth, causing active TB. This mini-review is aimed at summarizing the interplay of pathomechanisms in the macrophages and the implications of macrophage heterogeneity and plasticity during infection.
Topics: Humans; Immunity, Innate; Macrophages; Macrophages, Alveolar; Mycobacterium tuberculosis; Tuberculosis
PubMed: 35603185
DOI: 10.3389/fimmu.2022.747799 -
Blood Oct 2023In this spotlight, we review technical issues that compromise single-cell analysis of tissue macrophages, including limited and unrepresentative yields, fragmentation... (Review)
Review
In this spotlight, we review technical issues that compromise single-cell analysis of tissue macrophages, including limited and unrepresentative yields, fragmentation and generation of remnants, and activation during tissue disaggregation. These issues may lead to a misleading definition of subpopulations of macrophages and the expression of macrophage-specific transcripts by unrelated cells. Recognition of the technical limitations of single-cell approaches is required in order to map the full spectrum of tissue-resident macrophage heterogeneity and assess its biological significance.
Topics: Artifacts; Macrophages; Histiocytes
PubMed: 37595274
DOI: 10.1182/blood.2023020597 -
Frontiers in Immunology 2019Hepatic macrophages are a remarkably heterogeneous population consisting of self-renewing tissue-resident phagocytes, termed Kupffer cells (KCs), and recruited... (Review)
Review
Hepatic macrophages are a remarkably heterogeneous population consisting of self-renewing tissue-resident phagocytes, termed Kupffer cells (KCs), and recruited macrophages derived from peritoneal cavity as well as the bone marrow. KCs are located in the liver sinusoid where they scavenge the microbe from the portal vein to maintain liver homeostasis. Liver injury may trigger hepatic recruitment of peritoneal macrophages and monocyte-derived macrophages. Studies describing macrophage accumulation have shown that hepatic macrophages are involved in the initiation and progression of various liver diseases. They act as tolerogenic antigen-presenting cells to inhibit T-cell activation by producing distinct sets of cytokines, chemokines, and mediators to maintain or resolve inflammation. Furthermore, by releasing regenerative growth factors, matrix metalloproteinase arginase, they promote tissue repair. Recent experiments found that KCs and recruited macrophages may play different roles in the development of liver disease. Given that hepatic macrophages are considerably plastic populations, their phenotypes and functions are likely switching along disease progression. In this review, we summarize current knowledge about the role of tissue-resident macrophages and recruited macrophages in pathogenesis of alcoholic liver disease (ALD), non-alcoholic steatohepatitis (NASH), viral hepatitis, and hepatocellular carcinoma (HCC).
Topics: Biomarkers; Cell Communication; Cytokines; Disease Management; Disease Susceptibility; Humans; Immunophenotyping; Kupffer Cells; Liver Diseases; Macrophages; Molecular Targeted Therapy; Phenotype
PubMed: 32047496
DOI: 10.3389/fimmu.2019.03112 -
Frontiers in Immunology 2022Macrophages are essential innate immune cells that contribute to host defense during infection. An important feature of macrophages is their ability to respond to... (Review)
Review
Macrophages are essential innate immune cells that contribute to host defense during infection. An important feature of macrophages is their ability to respond to extracellular cues and to adopt different phenotypes and functions in response to these stimuli. The evidence accumulated in the last decade has highlighted the crucial role of metabolic reprogramming during macrophage activation in infectious context. Thus, understanding and manipulation of macrophage immunometabolism during infection could be of interest to develop therapeutic strategies. In this review, we focus on 5 major metabolic pathways including glycolysis, pentose phosphate pathway, fatty acid oxidation and synthesis, tricarboxylic acid cycle and amino acid metabolism and discuss how they sustain and regulate macrophage immune function in response to parasitic, bacterial and viral infections as well as trained immunity. At the end, we assess whether some drugs including those used in clinic and in development can target macrophage immunometabolism for potential therapy during infection with an emphasis on SARS-CoV2 infection.
Topics: Animals; COVID-19; Humans; Immunity, Innate; Infections; Macrophage Activation; Macrophages; SARS-CoV-2
PubMed: 35154105
DOI: 10.3389/fimmu.2022.780839 -
Advanced Materials (Deerfield Beach,... Mar 2021Human immune system acts as a pivotal role in the tissue homeostasis and disease progression. Immunomodulatory biomaterials that can manipulate innate immunity and... (Review)
Review
Human immune system acts as a pivotal role in the tissue homeostasis and disease progression. Immunomodulatory biomaterials that can manipulate innate immunity and adaptive immunity hold great promise for a broad range of prophylactic and therapeutic purposes. This review is focused on the design strategies and principles of immunomodulatory biomaterials from the standpoint of materials science to regulate macrophage fate, such as activation, polarization, adhesion, migration, proliferation, and secretion. It offers a comprehensive survey and discussion on the tunability of material designs regarding physical, chemical, biological, and dynamic cues for modulating macrophage immune response. The range of such tailorable cues encompasses surface properties, surface topography, materials mechanics, materials composition, and materials dynamics. The representative immunoengineering applications selected herein demonstrate how macrophage-immunomodulating biomaterials are being exploited for cancer immunotherapy, infection immunotherapy, tissue regeneration, inflammation resolution, and vaccination. A perspective on the future research directions of immunoregulatory biomaterials is also provided.
Topics: Animals; Biocompatible Materials; Humans; Immunologic Factors; Macrophages
PubMed: 33565154
DOI: 10.1002/adma.202004172