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The Journal of Experimental Medicine Jul 2023Macrophages play a central role in tissue homeostasis and host defense. However, the properties of human macrophages in non-diseased tissues remain poorly understood....
Macrophages play a central role in tissue homeostasis and host defense. However, the properties of human macrophages in non-diseased tissues remain poorly understood. Here, we characterized human tonsil macrophages and identified three subsets with distinct phenotype, transcriptome, life cycle, and function. CD36hi macrophages were related to monocytes, while CD36lo macrophages showed features of embryonic origin and CD36int macrophages had a mixed profile. scRNA-seq on non-human primate tonsils showed that monocyte recruitment did not pre-exist an immune challenge. Functionally, CD36hi macrophages were specialized for stimulating T follicular helper cells, by producing Activin A. Combining reconstruction of ligand-receptor interactions and functional assays, we identified stromal cell-derived TNF-α as an inducer of Activin A secretion. However, only CD36hi macrophages were primed for Activin A expression, via the activity of IRF1. Our results provide insight into the heterogeneity of human lymphoid organ macrophages and show that tonsil CD36hi macrophage specialization is the result of both intrinsic features and interaction with stromal cells.
Topics: Animals; Humans; Palatine Tonsil; Macrophages; Monocytes; Phenotype; Transcriptome
PubMed: 37036425
DOI: 10.1084/jem.20230002 -
International Journal of Molecular... Nov 2023Monocytes and macrophages are the innate immune cells that are the first-line responders to invading pathogens or foreign objects[...].
Monocytes and macrophages are the innate immune cells that are the first-line responders to invading pathogens or foreign objects[...].
Topics: Animals; Humans; Monocytes; Macrophages; Homeostasis; Immunity, Innate
PubMed: 38003587
DOI: 10.3390/ijms242216397 -
Cells May 2024Pulmonary surfactants play a crucial role in managing lung lipid metabolism, and dysregulation of this process is evident in various lung diseases. Alternations in lipid... (Review)
Review
Pulmonary surfactants play a crucial role in managing lung lipid metabolism, and dysregulation of this process is evident in various lung diseases. Alternations in lipid metabolism lead to pulmonary surfactant damage, resulting in hyperlipidemia in response to lung injury. Lung macrophages are responsible for recycling damaged lipid droplets to maintain lipid homeostasis. The inflammatory response triggered by external stimuli such as cigarette smoke, bleomycin, and bacteria can interfere with this process, resulting in the formation of lipid-laden macrophages (LLMs), also known as foamy macrophages. Recent studies have highlighted the potential significance of LLM formation in a range of pulmonary diseases. Furthermore, growing evidence suggests that LLMs are present in patients suffering from various pulmonary conditions. In this review, we summarize the essential metabolic and signaling pathways driving the LLM formation in chronic obstructive pulmonary disease, pulmonary fibrosis, tuberculosis, and acute lung injury.
Topics: Humans; Lung Diseases; Lipid Metabolism; Animals; Macrophages; Macrophages, Alveolar; Signal Transduction
PubMed: 38891022
DOI: 10.3390/cells13110889 -
Circulation Nov 2023Interferon-γ (IFNγ) signaling plays a complex role in atherogenesis. IFNγ stimulation of macrophages permits in vitro exploration of proinflammatory mechanisms and...
BACKGROUND
Interferon-γ (IFNγ) signaling plays a complex role in atherogenesis. IFNγ stimulation of macrophages permits in vitro exploration of proinflammatory mechanisms and the development of novel immune therapies. We hypothesized that the study of macrophage subpopulations could lead to anti-inflammatory interventions.
METHODS
Primary human macrophages activated by IFNγ (M(IFNγ)) underwent analyses by single-cell RNA sequencing, time-course cell-cluster proteomics, metabolite consumption, immunoassays, and functional tests (phagocytic, efferocytotic, and chemotactic). RNA-sequencing data were analyzed in LINCS (Library of Integrated Network-Based Cellular Signatures) to identify compounds targeting M(IFNγ) subpopulations. The effect of compound BI-2536 was tested in human macrophages in vitro and in a murine model of atherosclerosis.
RESULTS
Single-cell RNA sequencing identified 2 major clusters in M(IFNγ): inflammatory (M(IFNγ)) and phagocytic (M(IFNγ)). M(IFNγ) had elevated expression of inflammatory chemokines and higher amino acid consumption compared with M(IFNγ). M(IFNγ) were more phagocytotic and chemotactic with higher Krebs cycle activity and less glycolysis than M(IFNγ). Human carotid atherosclerotic plaques contained 2 such macrophage clusters. Bioinformatic LINCS analysis using our RNA-sequencing data identified BI-2536 as a potential compound to decrease the M(IFNγ) subpopulation. BI-2536 in vitro decreased inflammatory chemokine expression and secretion in M(IFNγ) by shrinking the M(IFNγ) subpopulation while expanding the M(IFNγ) subpopulation. BI-2536 in vivo shifted the phenotype of macrophages, modulated inflammation, and decreased atherosclerosis and calcification.
CONCLUSIONS
We characterized 2 clusters of macrophages in atherosclerosis and combined our cellular data with a cell-signature drug library to identify a novel compound that targets a subset of macrophages in atherosclerosis. Our approach is a precision medicine strategy to identify new drugs that target atherosclerosis and other inflammatory diseases.
Topics: Humans; Animals; Mice; Gene Regulatory Networks; Macrophages; Atherosclerosis; Plaque, Atherosclerotic; RNA; Biology
PubMed: 37850387
DOI: 10.1161/CIRCULATIONAHA.123.064794 -
International Immunopharmacology Oct 2023Neutrophils are a type of lymphocyte involved in innate immune defense. In response to specific stimuli, these phagocytic cells undergo a unique form of cell death,... (Review)
Review
Neutrophils are a type of lymphocyte involved in innate immune defense. In response to specific stimuli, these phagocytic cells undergo a unique form of cell death, NETosis, during which they release neutrophil extracellular traps (NETs) composed of modified chromatin structures decorated with cytoplasmic and granular proteins. Multiple proteins and pathways have been implicated in the formation of NETs. The cytoskeleton, an interconnected network of filamentous polymers and regulatory proteins, plays a crucial role in resisting deformation, transporting intracellular cargo, and changing shape during movement of eukaryotic cells. It may also have evolved to defend eukaryotic organisms against infection. Recent research focuses on understanding the mechanisms underlying NETs formation and how cytoskeletal networks contribute to this process, by identifying enzymes that trigger NETosis or interact with NETs and influence cellular behavior through cytoskeletal dynamics. An enhanced understanding of the complex relationship between the cytoskeleton and NET formation will provide a framework for future research and the development of targeted therapeutic strategies, and supports the notion that the long-lived cytoskeleton structures may have a lasting impact on this area of research.
Topics: Extracellular Traps; Cytoskeletal Proteins; Neutrophils; Phagocytosis; Cytoskeleton
PubMed: 37506501
DOI: 10.1016/j.intimp.2023.110607 -
Basic Research in Cardiology Feb 2024The development and rupture of atherosclerotic plaques is a major contributor to myocardial infarctions and ischemic strokes. The dynamic evolution of the plaque is... (Review)
Review
The development and rupture of atherosclerotic plaques is a major contributor to myocardial infarctions and ischemic strokes. The dynamic evolution of the plaque is largely attributed to monocyte/macrophage functions, which respond to various stimuli in the plaque microenvironment. To this end, macrophages play a central role in atherosclerotic lesions through the uptake of oxidized low-density lipoprotein that gets trapped in the artery wall, and the induction of an inflammatory response that can differentially affect the stability of the plaque in men and women. In this environment, macrophages can polarize towards pro-inflammatory M1 or anti-inflammatory M2 phenotypes, which represent the extremes of the polarization spectrum that include Mhem, M(Hb), Mox, and M4 populations. However, this traditional macrophage model paradigm has been redefined to include numerous immune and nonimmune cell clusters based on in-depth unbiased single-cell approaches. The goal of this review is to highlight (1) the phenotypic and functional properties of monocyte subsets in the circulation, and macrophage populations in atherosclerotic plaques, as well as their contribution towards stable or unstable phenotypes in men and women, and (2) single-cell RNA sequencing studies that have advanced our knowledge of immune, particularly macrophage signatures present in the atherosclerotic niche. We discuss the importance of performing high-dimensional approaches to facilitate the development of novel sex-specific immunotherapies that aim to reduce the risk of cardiovascular events.
Topics: Female; Humans; Plaque, Atherosclerotic; Macrophage Activation; Atherosclerosis; Macrophages; Monocytes
PubMed: 38244055
DOI: 10.1007/s00395-023-01023-z -
Infection and Immunity Nov 2023The pathogenic yeast represents a global threat of the utmost clinical relevance. This emerging fungal species is remarkable in its resistance to commonly used...
The pathogenic yeast represents a global threat of the utmost clinical relevance. This emerging fungal species is remarkable in its resistance to commonly used antifungal agents and its persistence in the nosocomial settings. The innate immune system is one the first lines of defense preventing the dissemination of pathogens in the host. is susceptible to circulating phagocytes, and understanding the molecular details of these interactions may suggest routes to improved therapies. In this work, we examined the interactions of this yeast with macrophages. We found that macrophages avidly phagocytose ; however, intracellular replication is not inhibited, indicating that resists the killing mechanisms imposed by the phagocyte. Unlike , phagocytosis of does not induce macrophage lysis. The transcriptional response of to macrophage phagocytosis is very similar to other members of the CUG clade (), i.e., downregulation of transcription/translation and upregulation of alternative carbon metabolism pathways, transporters, and induction of oxidative stress response and proteolysis. Gene family expansions are common in this yeast, and we found that many of these genes are induced in response to macrophage co-incubation. Among these, amino acid and oligopeptide transporters, as well as lipases and proteases, are upregulated. Thus, shares key transcriptional signatures shared with other fungal pathogens and capitalizes on the expansion of gene families coding for potential virulence attributes that allow its survival, persistence, and evasion of the innate immune system.
Topics: Candida; Candida auris; Candida albicans; Antifungal Agents; Macrophages; Candida parapsilosis
PubMed: 37815367
DOI: 10.1128/iai.00274-23 -
Immunological Reviews Mar 2024Since their description by Metchnikoff in 1905, phagocytes have been increasingly recognized to be the entities that traffic to sites of infection and inflammation,... (Review)
Review
Since their description by Metchnikoff in 1905, phagocytes have been increasingly recognized to be the entities that traffic to sites of infection and inflammation, engulf and kill infecting organisms, and clear out apoptotic debris all the while making antigens available and accessible to the lymphoid organs for future use. Therefore, phagocytes provide the gateway and the first check in host protection and immune response. Disorders in killing and chemotaxis lead not only to infection susceptibility, but also to autoimmunity. We aim to describe chronic granulomatous disease and the leukocyte adhesion deficiencies as well as myeloperoxidase deficiency and G6PD deficiency as paradigms of critical pathways.
Topics: Humans; Neutrophils; Granulomatous Disease, Chronic; Phagocytosis; Phagocytes; Inflammation
PubMed: 38429865
DOI: 10.1111/imr.13308 -
British Journal of Pharmacology May 2024Human neutrophils are components of the innate immune system and are the most abundant white blood cells in the circulation. They are professional phagocytes and express... (Review)
Review
Human neutrophils are components of the innate immune system and are the most abundant white blood cells in the circulation. They are professional phagocytes and express several G protein-coupled receptors (GPCRs), which are essential for proper neutrophil functions. So far, the two formyl peptide receptors, FPR1 and FPR2, have been the most extensively studied group of neutrophil GPCRs, but recently, a new group, the free fatty acid (FFA) receptors, has attracted growing attention. Neutrophils express two FFA receptors, GPR84 and FFA2, which sense medium- and short-chain fatty acids respectively, and display similar activation profiles. The exact pathophysiological role of GPR84 is not yet fully understood, but it is generally regarded as a pro-inflammatory receptor that mediates neutrophil activation. In this review, we summarize current knowledge of how GPR84 affects human neutrophil functions and discuss the regulatory mechanisms that control these responses, focusing on the similarities and differences in comparison to the two FPRs and FFA2. LINKED ARTICLES: This article is part of a themed issue GPR84 Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.10/issuetoc.
Topics: Humans; Neutrophils; Signal Transduction; Receptors, Formyl Peptide; Phagocytes; Receptors, G-Protein-Coupled
PubMed: 36869866
DOI: 10.1111/bph.16066 -
Lactate-Responsive Gene Editing to Synergistically Enhance Macrophage-Mediated Cancer Immunotherapy.Small (Weinheim An Der Bergstrasse,... Aug 2023Combination therapies involving metabolic regulation and immune checkpoint blockade are considered an encouraging new strategy for cancer therapy. However, the effective...
Combination therapies involving metabolic regulation and immune checkpoint blockade are considered an encouraging new strategy for cancer therapy. However, the effective utilization of combination therapies for activating tumor-associated macrophages (TAMs) remains challenging. Herein, a lactate-catalyzed chemodynamic approach to activate the therapeutic genome editing of signal-regulatory protein α (SIRPα) to reprogram TAMs and improve cancer immunotherapy is proposed. This system is constructed by encapsulating lactate oxidase (LOx) and clustered regularly interspaced short palindromic repeat-mediated SIRPα genome-editing plasmids in a metal-organic framework (MOF). The genome-editing system is released and activated by acidic pyruvate, which is produced by the LOx-catalyzed oxidation of lactate. The synergy between lactate exhaustion and SIRPα signal blockade can enhance the phagocytic ability of TAMs and promote the repolarization of TAMs to the antitumorigenic M1 phenotype. Lactate exhaustion-induced CD47-SIRPα blockade efficiently improves macrophage antitumor immune responses and effectively reverses the immunosuppressive tumor microenvironment to inhibit tumor growth, as demonstrated by in vitro and in vivo studies. This study provides a facile strategy for engineering TAMs in situ by combining CRISPR-mediated SIRPα knockout with lactate exhaustion for effective immunotherapy.
Topics: Humans; Gene Editing; Lactic Acid; Macrophages; Neoplasms; Immunotherapy; Tumor Microenvironment
PubMed: 37156740
DOI: 10.1002/smll.202301519