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Journal of Hematology & Oncology Jul 2023Tumour-associated macrophages (TAMs) are crucial components of the tumour microenvironment and play a significant role in tumour development and drug resistance by... (Review)
Review
Tumour-associated macrophages (TAMs) are crucial components of the tumour microenvironment and play a significant role in tumour development and drug resistance by creating an immunosuppressive microenvironment. Macrophages are essential components of both the innate and adaptive immune systems and contribute to pathogen resistance and the regulation of organism homeostasis. Macrophage function and polarization are closely linked to altered metabolism. Generally, M1 macrophages rely primarily on aerobic glycolysis, whereas M2 macrophages depend on oxidative metabolism. Metabolic studies have revealed that the metabolic signature of TAMs and metabolites in the tumour microenvironment regulate the function and polarization of TAMs. However, the precise effects of metabolic reprogramming on tumours and TAMs remain incompletely understood. In this review, we discuss the impact of metabolic pathways on macrophage function and polarization as well as potential strategies for reprogramming macrophage metabolism in cancer treatment.
Topics: Humans; Macrophages; Neoplasms; Tumor-Associated Macrophages; Metabolic Networks and Pathways; Tumor Microenvironment
PubMed: 37491279
DOI: 10.1186/s13045-023-01478-6 -
Cell Sep 2023Macrophages are heterogeneous and play critical roles in development and disease, but their diversity, function, and specification remain inadequately understood during...
Macrophages are heterogeneous and play critical roles in development and disease, but their diversity, function, and specification remain inadequately understood during human development. We generated a single-cell RNA sequencing map of the dynamics of human macrophage specification from PCW 4-26 across 19 tissues. We identified a microglia-like population and a proangiogenic population in 15 macrophage subtypes. Microglia-like cells, molecularly and morphologically similar to microglia in the CNS, are present in the fetal epidermis, testicle, and heart. They are the major immune population in the early epidermis, exhibit a polarized distribution along the dorsal-lateral-ventral axis, and interact with neural crest cells, modulating their differentiation along the melanocyte lineage. Through spatial and differentiation trajectory analysis, we also showed that proangiogenic macrophages are perivascular across fetal organs and likely yolk-sac-derived as microglia. Our study provides a comprehensive map of the heterogeneity and developmental dynamics of human macrophages and unravels their diverse functions during development.
Topics: Humans; Cell Differentiation; Cell Lineage; Macrophages; Microglia; Organ Specificity
PubMed: 37703875
DOI: 10.1016/j.cell.2023.08.019 -
Cell Communication and Signaling : CCS Dec 2023The growing prevalence of inflammatory bowel disease (IBD) has encouraged research efforts, which have contributed to gradual improvements in our understanding of IBD... (Review)
Review
The growing prevalence of inflammatory bowel disease (IBD) has encouraged research efforts, which have contributed to gradual improvements in our understanding of IBD diagnosis and therapeutic approaches. The pathogenesis of IBD has not been fully elucidated; however, the combined actions of environmental, genetic, immune factors, and microbial organisms are believed to cause IBD. In the innate immune system, macrophages play important roles in maintaining intestinal health and in the development of IBD. Macrophages can be polarized from M0 into several phenotypes, among which M1 and M2 play critical roles in IBD development and the repair of intestinal homeostasis and damage. Certain macrophage-related IBD studies already exist; however, the functions of each phenotype have not been fully elucidated. As technology develops, understanding the link between macrophages and IBD has increased, including the growing knowledge of the developmental origins of intestinal macrophages and their performance of comprehensive functions. This review describes macrophage polarization in IBD from the perspectives of macrophage development and polarization, macrophage changes in homeostasis and IBD, metabolic changes, and the mechanisms of macrophage polarization in IBD. The discussion of these topics provides new insights into immunotherapy strategies for IBD. Video Abstract.
Topics: Humans; Inflammatory Bowel Diseases; Macrophages; Intestines; Phenotype
PubMed: 38129886
DOI: 10.1186/s12964-023-01386-9 -
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 -
Immunological Reviews Oct 2023The phagocytosis of dying cells by macrophages, termed efferocytosis, is a tightly regulated process that involves the sensing, binding, engulfment, and digestion of... (Review)
Review
The phagocytosis of dying cells by macrophages, termed efferocytosis, is a tightly regulated process that involves the sensing, binding, engulfment, and digestion of apoptotic cells. Efferocytosis not only prevents tissue necrosis and inflammation caused by secondary necrosis of dying cells, but it also promotes pro-resolving signaling in macrophages, which is essential for tissue resolution and repair following injury or inflammation. An important factor that contributes to this pro-resolving reprogramming is the cargo that is released from apoptotic cells after their engulfment and phagolysosomal digestion by macrophages. The apoptotic cell cargo contains amino acids, nucleotides, fatty acids, and cholesterol that function as metabolites and signaling molecules to bring about this re-programming. Here, we review efferocytosis-induced changes in macrophage metabolism that mediate the pro-resolving functions of macrophages. We also discuss various strategies, challenges, and future perspectives related to drugging efferocytosis-fueled macrophage metabolism as strategy to dampen inflammation and promote resolution in chronic inflammatory diseases.
Topics: Humans; Apoptosis; Phagocytosis; Macrophages; Inflammation; Necrosis
PubMed: 37158427
DOI: 10.1111/imr.13214 -
Trends in Immunology Dec 2023Macrophages represent a key component of the tumor microenvironment (TME) and are largely associated with poor prognosis. Therapeutic targeting of macrophages has... (Review)
Review
Macrophages represent a key component of the tumor microenvironment (TME) and are largely associated with poor prognosis. Therapeutic targeting of macrophages has historically focused on inhibiting their recruitment or reprogramming their phenotype from a protumor (M2-like) to an antitumor (M1-like) one. Unfortunately, this approach has not provided clinical breakthroughs that have changed practice. Emerging studies utilizing single-cell RNA-sequencing (scRNA-seq) and spatial transcriptomics have improved our understanding of the ontogeny, phenotype, and functional plasticity of macrophages. Overlaying the wealth of current information regarding macrophage molecular subtypes and functions has also identified novel therapeutic vulnerabilities that might drive better control of tumor-associated macrophages (TAMs). Here, we discuss the functional profiling of macrophages and provide an update of novel macrophage-targeted therapies in development.
Topics: Humans; Neoplasms; Macrophages; Phenotype; Tumor Microenvironment
PubMed: 37995659
DOI: 10.1016/j.it.2023.10.007 -
Journal For Immunotherapy of Cancer Aug 2023Massive tumor-associated macrophage (TAM) infiltration is observed in many tumors, which usually display the immune-suppressive M2-like phenotype but can also be...
BACKGROUND
Massive tumor-associated macrophage (TAM) infiltration is observed in many tumors, which usually display the immune-suppressive M2-like phenotype but can also be converted to an M1-like antitumor phenotype due to their high degree of plasticity. The macrophage polarization state is associated with changes in cell shape, macrophage morphology is associated with activation status. M1 macrophages appeared large and rounded, while M2 macrophages were stretched and elongated cells. Manipulating cell morphology has been shown to affect the polarization state of macrophages. The shape of the cell is largely dependent on cytoskeletal proteins, especially, microtubules. As a microtubule-targetting drug, vinblastine (VBL) has been used in chemotherapy. However, no study to date has explored the effect of VBL on TAM shape changes and its role in tumor immune response.
METHOD
We used fluorescent staining of the cytoskeleton and quantitative analysis to reveal the morphological differences between M0, M1, M2, TAM and VBL-treated TAM. Flow cytometry was used to confirm the polarization states of these macrophages using a cell surface marker-based classification. In vivo antibody depletion experiments in tumor mouse models were performed to test whether macrophages and CD8 T cell populations were required for the antitumor effect of VBL. VBL and anti-PD-1 combination therapy was then investigated in comparison with monotherapy. RNA-seq of TAM of treated and untreated with VBL was performed to explore the changes in pathway activities. siRNA mediated knockdown experiments were performed to verify the target pathway that was affected by VBL treatment.
RESULTS
Here, we showed that VBL, an antineoplastic agent that destabilizes microtubule, drove macrophage polarization into the M1-like phenotype both in vitro and in tumor models. The antitumor effect of VBL was attenuated in the absence of macrophages or CD8 T cells. Mechanistically, VBL induces the activation of NF-κB and Cyba-dependent reactive oxygen species generation, thus polarizing TAMs to the M1 phenotype. In parallel, VBL promotes the nuclear translocation of transcription factor EB, inducing lysosome biogenesis and a dramatic increase in phagocytic activity in macrophages.
CONCLUSIONS
This study explored whether manipulating cellular morphology affects macrophage polarization and consequently induces an antitumor response. Our data reveal a previously unrecognized antitumor mechanism of VBL and suggest a drug repurposing strategy combining VBL with immune checkpoint inhibitors to improve malignant tumor immunotherapy.
Topics: Animals; Mice; Tumor-Associated Macrophages; Vinblastine; CD8-Positive T-Lymphocytes; Macrophages; Immunity
PubMed: 37652576
DOI: 10.1136/jitc-2023-007253 -
Cell Reports Nov 2023Macroautophagy/autophagy plays a pivotal role in immune regulation. Its significance is evident in modulation of immune cell differentiation and maturation,...
Macroautophagy/autophagy plays a pivotal role in immune regulation. Its significance is evident in modulation of immune cell differentiation and maturation, physiologically and pathologically. Here, we investigate the role of macrophage autophagy on the development of atopic dermatitis (AD). By employing an MC903-induced AD mice model, we observe reduced cutaneous inflammation in macrophage Atg5 cKO mice compared with WT mice. Notably, there is a decreased infiltration of M2 macrophages in lesional skin from Atg5 cKO mice. Furthermore, impaired STAT6 phosphorylation and diminished expression of M2 markers are detected in autophagy-deficient macrophages. Our mechanistic exploration reveals that CEBPB drives the transcription of SOCS1/3 and SQSTM1/p62-mediated autophagy degrades CEBPB normally. Autophagy deficiency leads to CEBPB accumulation, and further promotes the expression of SOCS1/3. This process inhibits JAK1-STAT6 pathway activation and M2 marker expression. Together, our study indicates that autophagy is required for M2 activation and macrophage autophagy may be a promising target for AD intervention.
Topics: Animals; Mice; Autophagy; Dermatitis, Atopic; Disease Models, Animal; Macrophage Activation; Macrophages
PubMed: 37963021
DOI: 10.1016/j.celrep.2023.113430 -
Circulation Research Mar 2024Many cardiovascular pathologies are induced by signaling through G-protein-coupled receptors via Gsα (G protein stimulatory α subunit) proteins. However, the specific...
BACKGROUND
Many cardiovascular pathologies are induced by signaling through G-protein-coupled receptors via Gsα (G protein stimulatory α subunit) proteins. However, the specific cellular mechanisms that are driven by Gsα and contribute to the development of atherosclerosis remain unclear.
METHODS
High-throughput screening involving data from single-cell and bulk sequencing were used to explore the expression of Gsα in atherosclerosis. The differentially expression and activity of Gsα were analyzed by immunofluorescence and cAMP measurements. Macrophage-specific Gsα knockout (Mac-Gsα) mice were generated to study the effect on atherosclerosis. The role of Gsα was determined by transplanting bone marrow and performing assays for foam cell formation, Dil-ox-LDL (oxidized low-density lipoprotein) uptake, chromatin immunoprecipitation, and luciferase reporter assays.
RESULTS
ScRNA-seq showed elevated in atherosclerotic mouse aorta's cholesterol metabolism macrophage cluster, while bulk sequencing confirmed increased expression in human plaque macrophage content. A significant upregulation of Gsα and active Gsα occurred in macrophages from human and mouse plaques. Ox-LDL could translocate Gsα from macrophage lipid rafts in short-term and promote transcription through ERK1/2 activation and C/EBPβ phosphorylation via oxidative stress in long-term. Atherosclerotic lesions from Mac-Gsα mice displayed decreased lipid deposition compared with those from control mice. Additionally, Gsα deficiency alleviated lipid uptake and foam cell formation. Mechanistically, Gsα increased the levels of cAMP and transcriptional activity of the cAMP response element binding protein, which resulted in increased expression of CD36 and SR-A1. In the translational experiments, inhibiting Gsα activation with suramin or cpGN13 reduced lipid uptake, foam cell formation, and the progression of atherosclerotic plaques in mice in vivo.
CONCLUSIONS
Gsα activation is enhanced during atherosclerotic progression and increases lipid uptake and foam cell formation. The genetic or chemical inactivation of Gsα inhibit the development of atherosclerosis in mice, suggesting that drugs targeting Gsα may be useful in the treatment of atherosclerosis.
Topics: Animals; Humans; Mice; Atherosclerosis; Foam Cells; Lipoproteins, LDL; Macrophages; Plaque, Atherosclerotic; Signal Transduction
PubMed: 38375634
DOI: 10.1161/CIRCRESAHA.123.323156 -
Inflammation Aug 2023With advances in immunometabolic studies, more and more evidence has shown that metabolic changes profoundly affect the immune function of macrophages. The tricarboxylic... (Review)
Review
With advances in immunometabolic studies, more and more evidence has shown that metabolic changes profoundly affect the immune function of macrophages. The tricarboxylic acid cycle is a central metabolic pathway of cells. Itaconate, a byproduct of the tricarboxylic acid cycle, is an emerging metabolic small molecule that regulates macrophage inflammation and has received much attention for its potent anti-inflammatory effects in recent years. Itaconate regulates macrophage function through multiple mechanisms and has demonstrated promising therapeutic potential in a variety of immune and inflammatory diseases. New progress in the mechanism of itaconate continues to be made, but it also implies complexity in its action and a need for a more comprehensive understanding of its role in macrophages. In this article, we review the primary mechanisms and current research progress of itaconate in regulating macrophage immune metabolism, hoping to provide new insights and directions for future research and disease treatment.
Topics: Succinates; Macrophages; Adjuvants, Immunologic; Immunologic Factors
PubMed: 37142886
DOI: 10.1007/s10753-023-01819-0