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Cells May 2021Phagocytosis by glial cells has been shown to play an important role in maintaining brain homeostasis. Microglia are currently considered to be the major phagocytes in... (Review)
Review
Phagocytosis by glial cells has been shown to play an important role in maintaining brain homeostasis. Microglia are currently considered to be the major phagocytes in the brain parenchyma, and these cells phagocytose a variety of materials, including dead cell debris, abnormally aggregated proteins, and, interestingly, the functional synapses of living neurons. The intracellular signaling mechanisms that regulate microglial phagocytosis have been studied extensively, and several important factors, including molecules known as "find me" signals and "eat me" signals and receptors on microglia that are involved in phagocytosis, have been identified. In addition, recent studies have revealed that astrocytes, which are another major glial cell in the brain parenchyma, also have phagocytic abilities. In this review, we will discuss the roles of microglia and astrocytes in phagocytosis-mediated brain homeostasis, focusing on the characteristics and differences of their phagocytic abilities.
Topics: Animals; Astrocytes; Brain; Homeostasis; Humans; Neuroglia; Neurons; Phagocytes
PubMed: 34072424
DOI: 10.3390/cells10061348 -
Nature Communications Sep 2023GPR84 is a unique orphan G protein-coupled receptor (GPCR) that can be activated by endogenous medium-chain fatty acids (MCFAs). The signaling of GPR84 is largely...
GPR84 is a unique orphan G protein-coupled receptor (GPCR) that can be activated by endogenous medium-chain fatty acids (MCFAs). The signaling of GPR84 is largely pro-inflammatory, which can augment inflammatory response, and GPR84 also functions as a pro-phagocytic receptor to enhance phagocytic activities of macrophages. In this study, we show that the activation of GPR84 by the synthetic agonist 6-OAU can synergize with the blockade of CD47 on cancer cells to induce phagocytosis of cancer cells by macrophages. We also determine a high-resolution structure of the GPR84-G signaling complex with 6-OAU. This structure reveals an occluded binding pocket for 6-OAU, the molecular basis of receptor activation involving non-conserved structural motifs of GPR84, and an unusual G-coupling interface. Together with computational docking and simulations studies, this structure also suggests a mechanism for the high selectivity of GPR84 for MCFAs and a potential routes of ligand binding and dissociation. These results provide a framework for understanding GPR84 signaling and developing new drugs targeting GPR84.
Topics: Phagocytes; Signal Transduction; Macrophages; Phagocytosis; Fatty Acids
PubMed: 37709767
DOI: 10.1038/s41467-023-41201-0 -
Nature Communications Jul 2023Endo-lysosomes transport along microtubules and clustering in the perinuclear area are two necessary steps for microbes to activate specialized phagocyte functions. We...
Endo-lysosomes transport along microtubules and clustering in the perinuclear area are two necessary steps for microbes to activate specialized phagocyte functions. We report that RUN and FYVE domain-containing protein 3 (RUFY3) exists as two alternative isoforms distinguishable by the presence of a C-terminal FYVE domain and by their affinity for phosphatidylinositol 3-phosphate on endosomal membranes. The FYVE domain-bearing isoform (iRUFY3) is preferentially expressed in primary immune cells and up-regulated upon activation by microbes and Interferons. iRUFY3 is necessary for ARL8b + /LAMP1+ endo-lysosomes positioning in the pericentriolar organelles cloud of LPS-activated macrophages. We show that iRUFY3 controls macrophages migration, MHC II presentation and responses to Interferon-γ, while being important for intracellular Salmonella replication. Specific inactivation of rufy3 in phagocytes leads to aggravated pathologies in mouse upon LPS injection or bacterial pneumonia. This study highlights the role of iRUFY3 in controlling endo-lysosomal dynamics, which contributes to phagocyte activation and immune response regulation.
Topics: Animals; Mice; Antigen Presentation; Endosomes; Lipopolysaccharides; Lysosomes; Phagocytes
PubMed: 37463962
DOI: 10.1038/s41467-023-40062-x -
Journal of Leukocyte Biology Aug 2021Discussion on the molecular mechanism of phagocyte NADPH oxidase activation.
Discussion on the molecular mechanism of phagocyte NADPH oxidase activation.
Topics: Humans; NADPH Oxidases; Phagocytes; Phosphoproteins
PubMed: 33993516
DOI: 10.1002/JLB.4CE0321-134R -
Frontiers in Immunology 2020Phagocytes are highly motile immune cells that ingest and clear microbial invaders, harmful substances, and dying cells. Their function is critically dependent on the... (Review)
Review
Phagocytes are highly motile immune cells that ingest and clear microbial invaders, harmful substances, and dying cells. Their function is critically dependent on the expression of chemokine receptors, a class of G-protein-coupled receptors (GPCRs). Chemokine receptors coordinate the recruitment of phagocytes and other immune cells to sites of infection and damage, modulate inflammatory and wound healing responses, and direct cell differentiation, proliferation, and polarization. Besides, a structurally diverse group of atypical chemokine receptors (ACKRs) are unable to signal in G-protein-dependent fashion themselves but can shape chemokine gradients by fine-tuning the activity of conventional chemokine receptors. The optically transparent zebrafish embryos and larvae provide a powerful system to visualize phagocytes during development and study them as key elements of the immune response in real-time. In this review, we discuss how the zebrafish model has furthered our understanding of the role of two main classes of chemokine receptors, the CC and CXC subtypes, in phagocyte biology. We address the roles of the receptors in the migratory properties of phagocytes in zebrafish models for cancer, infectious disease, and inflammation. We illustrate how studies in zebrafish enable visualizing the contribution of chemokine receptors and ACKRs in shaping self-generated chemokine gradients of migrating cells. Taking the functional antagonism between two paralogs of the CXCR3 family as an example, we discuss how the duplication of chemokine receptor genes in zebrafish poses challenges, but also provides opportunities to study sub-functionalization or loss-of-function events. We emphasize how the zebrafish model has been instrumental to prove that the major determinant for the functional outcome of a chemokine receptor-ligand interaction is the cell-type expressing the receptor. Finally, we highlight relevant homologies and analogies between mammalian and zebrafish phagocyte function and discuss the potential of zebrafish models to further advance our understanding of chemokine receptors in innate immunity and disease.
Topics: Animals; Humans; Immunity, Innate; Inflammation; Macrophages; Neoplasms; Phagocytes; Receptors, Chemokine; Wounds and Injuries; Zebrafish
PubMed: 32161595
DOI: 10.3389/fimmu.2020.00325 -
Sub-cellular Biochemistry 2022Phagocytes play critical roles in the maintenance of organismal homeostasis and immunity. Central to their role is their ability to take up and process exogenous...
Phagocytes play critical roles in the maintenance of organismal homeostasis and immunity. Central to their role is their ability to take up and process exogenous material via the related processes of phagocytosis and macropinocytosis. The mechanisms and functions underlying macropinocytosis have remained severely understudied relative to phagocytosis. In recent years, however, there has been a renaissance in macropinocytosis research. Phagocytes can engage in various forms of macropinocytosis including an "induced" form and a "constitutive" form. This chapter, however, will focus on constitutive macropinocytosis and its role in the maintenance of immunity. Functions previously attributed to macropinocytosis, including antigen presentation and immune surveillance, will be revisited in light of recent revelations and emerging concepts will be highlighted.
Topics: Antigen Presentation; Homeostasis; Phagocytes; Phagocytosis; Pinocytosis
PubMed: 35378705
DOI: 10.1007/978-3-030-94004-1_6 -
Current Biology : CB Jan 2021New work shows that the glycocalyx meshwork on the surface of macrophages prevents phagocytic receptors from binding their ligands by two means - electrostatic charge...
New work shows that the glycocalyx meshwork on the surface of macrophages prevents phagocytic receptors from binding their ligands by two means - electrostatic charge and steric hindrance. Components of this barrier are present on pathogenic and malignant targets that elude phagocytosis.
Topics: Glycocalyx; Ligands; Macrophages; Phagocytes; Phagocytosis
PubMed: 33434480
DOI: 10.1016/j.cub.2020.10.066 -
Methods in Molecular Biology (Clifton,... 2023Phagocytosis is relevant for many research fields and is often measured as a functional outcome. However, accurate quantification can be challenging, and many...
Phagocytosis is relevant for many research fields and is often measured as a functional outcome. However, accurate quantification can be challenging, and many researchers find it difficult to study in a robust manner. There are many ways to measure phagocytosis, but what is often overlooked is the importance of experimental design and how the analysis is planned and performed. Experimental factors like reaction volume, time, and phagocyte-prey concentrations often have a large impact on the outcome, as is the choice of detection strategy with different fluorescent or colorimetric labels of prey and phagocyte. By using dose-response curve principles for both experimental design and analysis, it is possible to increase the sensitivity and robustness, leading to accurate quantification of phagocytosis that is comparable across experiments and systems.Here, we describe how to quantify phagocytosis using flow cytometry with a robust, high-throughput, and easy-to-use approach. The prey is first fluorescently double stained, followed by optional opsonization before being introduced to the phagocyte in a wide range of ratios. After incubation, data is acquired through flow cytometry. It can be assessed on both the population and single-cell level of the phagocytes, separating adhesion and internalization. As an example, we provide an experimental protocol for studying phagocytosis of opsonized Streptococcus pyogenes using the THP-1 cell line. This approach is easily incorporated into most existing phagocytosis assays and allows for reproducible results with high sensitivity.
Topics: Flow Cytometry; Phagocytosis; Phagocytes; Coloring Agents; Streptococcus pyogenes
PubMed: 37258971
DOI: 10.1007/978-1-0716-3243-7_15 -
Development (Cambridge, England) Apr 2022Although best known for their phagocytic and immunological functions, macrophages have increasingly been recognised as key players in the development, homeostasis and...
Although best known for their phagocytic and immunological functions, macrophages have increasingly been recognised as key players in the development, homeostasis and regeneration of their host tissues. Early during development, macrophages infiltrate and colonise all tissues within the body, developing symbiotically with their host tissues and acquiring unique functional adaptations based on the tissue microenvironment. These embryonic resident tissue macrophages (RTMs) are ontogenically distinct from the later adult bone marrow-derived monocytes, and in some tissues are self-maintained independently of general circulation at a steady state. In this article, we briefly discuss the ontogeny, maintenance and unique tissue adaptions of RTMs focusing on microglia, Kupffer cells, Langerhans cells, intestinal macrophages, cardiac macrophages and tumour-associated macrophages, and highlight their role in development, homeostasis and dysfunction.
Topics: Biology; Cell Differentiation; Macrophages; Microglia; Monocytes
PubMed: 35502781
DOI: 10.1242/dev.200270 -
Immunological Reviews Oct 2023The clearance of dead and dying cells, termed efferocytosis, is a rapid and efficient process and one that is critical for organismal health. The extraordinary speed and... (Review)
Review
The clearance of dead and dying cells, termed efferocytosis, is a rapid and efficient process and one that is critical for organismal health. The extraordinary speed and efficiency with which dead cells are detected and engulfed by immune cells within tissues presents a challenge to researchers who wish to unravel this fascinating process, since these fleeting moments of uptake are almost impossible to catch in vivo. In recent years, the fruit fly (Drosophila melanogaster) embryo has emerged as a powerful model to circumvent this problem. With its abundance of dying cells, specialist phagocytes and relative ease of live imaging, the humble fly embryo provides a unique opportunity to catch and study the moment of cell engulfment in real-time within a living animal. In this review, we explore the recent advances that have come from studies in the fly, and how live imaging and genetics have revealed a previously unappreciated level of diversity in the efferocytic program. A variety of efferocytic strategies across the phagocytic cell population ensure efficient and rapid clearance of corpses wherever death is encountered within the varied and complex setting of a multicellular living organism.
Topics: Animals; Humans; Drosophila melanogaster; Apoptosis; Phagocytosis; Phagocytes; Drosophila
PubMed: 37589239
DOI: 10.1111/imr.13266