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Nature Reviews. Immunology May 2021Cell death occurs when a pathogen invades a host organism or the organism is subjected to sterile injury. Thus, cell death is often closely associated with the induction... (Review)
Review
Cell death occurs when a pathogen invades a host organism or the organism is subjected to sterile injury. Thus, cell death is often closely associated with the induction of an immune response. Furthermore, cell death can occur as a consequence of the immune response and precedes the tissue renewal and repair responses that are initiated by innate immune cells during resolution of an immune response. Beyond immunity, cell death is required for development, morphogenesis and homeostasis. How can such a ubiquitous event as cell death trigger such a wide range of context-specific effector responses? Dying cells are sensed by innate immune cells using specialized receptors and phagocytosed through a process termed efferocytosis. Here, we outline a general principle whereby signals within the dead cell as well as the environment are integrated by specific efferocytes to define the appropriate effector response.
Topics: Animals; Cell Death; Cellular Microenvironment; Cytokines; Homeostasis; Host-Pathogen Interactions; Humans; Immunity, Innate; Mathematical Concepts; Models, Immunological; Phagocytes; Phagocytosis; Signal Transduction
PubMed: 33188303
DOI: 10.1038/s41577-020-00456-0 -
Cold Spring Harbor Perspectives in... Apr 2020Multicellular organisms are not created through cell proliferation alone. It is through cell death that an indefinite cellular mass is pared back to reveal its true... (Review)
Review
Multicellular organisms are not created through cell proliferation alone. It is through cell death that an indefinite cellular mass is pared back to reveal its true form. Cells are also lost throughout life as part of homeostasis and through injury. This detritus represents a significant burden to the living organism and must be cleared, most notably through the use of specialized phagocytic cells. Our understanding of these phagocytes and how they engulf cell corpses has been greatly aided by studying the fruit fly, Here we review the contribution of research to our understanding of how phagocytes respond to cell death. We focus on the best studied phagocytes in the fly: the glia of the central nervous system, the ovarian follicle cells, and the macrophage-like hemocytes. Each is explored in the context of the tissue they maintain as well as how they function during development and in response to injury.
Topics: Animals; Apoptosis; Astrocytes; Cell Death; Cell Proliferation; Central Nervous System; Drosophila Proteins; Drosophila melanogaster; Female; Hemocytes; Homeostasis; Inflammation; Macrophages; Neuroglia; Ovarian Follicle; Phagocytes; Phagocytosis
PubMed: 31501193
DOI: 10.1101/cshperspect.a036350 -
Advanced Science (Weinheim,... Apr 2023Large peritoneal macrophages (LPMs) are long-lived, tissue-resident macrophages, formed during embryonic life, developmentally and functionally confined to the... (Review)
Review
Large peritoneal macrophages (LPMs) are long-lived, tissue-resident macrophages, formed during embryonic life, developmentally and functionally confined to the peritoneal cavity. LPMs provide the first line of defense against life-threatening pathologies of the peritoneal cavity, such as abdominal sepsis, peritoneal metastatic tumor growth, or peritoneal injuries caused by trauma, or abdominal surgery. Apart from their primary phagocytic function, reminiscent of primitive defense mechanisms sustained by coelomocytes in the coelomic cavity of invertebrates, LPMs fulfill an essential homeostatic function by achieving an efficient clearance of apoptotic, that is crucial for the maintenance of self-tolerance. Research performed over the last few years, in mice, has unveiled the mechanisms by which LPMs fulfill a crucial role in repairing peritoneal injuries and controlling microbial and parasitic infections, reflecting that the GATA6-driven LPM transcriptional program can be modulated by extracellular signals associated with pathological conditions. In contrast, recent experimental evidence supports that peritoneal tumors can subvert LPM metabolism and function, leading to the acquisition of a tumor-promoting potential. The remarkable functional plasticity of LPMs can be nevertheless exploited to revert tumor-induced LPM protumor potential, providing the basis for the development of novel immunotherapeutic approaches against peritoneal tumor metastasis based on macrophage reprogramming.
Topics: Animals; Mice; Macrophages, Peritoneal; Macrophages; Homeostasis
PubMed: 36658699
DOI: 10.1002/advs.202206617 -
Frontiers in Immunology 2021Phagocytosis is the cellular defense mechanism used to eliminate antigens derived from dysregulated or damaged cells, and microbial pathogens. Phagocytosis is therefore...
Phagocytosis is the cellular defense mechanism used to eliminate antigens derived from dysregulated or damaged cells, and microbial pathogens. Phagocytosis is therefore a pillar of innate immunity, whereby foreign particles are engulfed and degraded in lysolitic vesicles. In hexacorallians, phagocytic mechanisms are poorly understood, though putative anthozoan phagocytic cells (amoebocytes) have been identified histologically. We identify and characterize phagocytes from the coral and the sea anemone . Using fluorescence-activated cell sorting and microscopy, we show that distinct populations of phagocytic cells engulf bacteria, fungal antigens, and beads. In addition to pathogenic antigens, we show that phagocytic cells engulf self, damaged cells. We show that target antigens localize to low pH phagolysosomes, and that degradation is occurring within them. Inhibiting actin filament rearrangement interferes with efficient particle phagocytosis but does not affect small molecule pinocytosis. We also demonstrate that cellular markers for lysolitic vesicles and reactive oxygen species (ROS) correlate with hexacorallian phagocytes. These results establish a foundation for improving our understanding of hexacorallian immune cell biology.
Topics: Animals; Anthozoa; Biomarkers; Cytokines; Cytoplasmic Vesicles; Flow Cytometry; Hydrogen-Ion Concentration; Immunity, Innate; Phagocytes; Phagocytosis; Phagosomes; Sea Anemones
PubMed: 34381444
DOI: 10.3389/fimmu.2021.662803 -
Frontiers in Immunology 2020
Topics: Animals; Phagocytes
PubMed: 33362804
DOI: 10.3389/fimmu.2020.628847 -
Current Opinion in Cell Biology Oct 2020Phagocytosis is a widespread and evolutionarily conserved process with diverse biological functions, ranging from engulfment of invading microbes during infection to... (Review)
Review
Phagocytosis is a widespread and evolutionarily conserved process with diverse biological functions, ranging from engulfment of invading microbes during infection to clearance of apoptotic debris in tissue homeostasis. Along with differences in biochemical composition, phagocytic targets greatly differ in physical attributes, such as size, shape, and rigidity, which are now recognized as important regulators of this process. Force exertion at the cell-target interface and cellular mechanical changes during phagocytosis are emerging as crucial factors underlying sensing of such target properties. With technological developments, mechanical aspects of phagocytosis are increasingly accessible experimentally, revealing remarkable organizational complexity of force exertion. An increasingly high-resolution picture is emerging of how target physical cues and cellular mechanical properties jointly govern important steps throughout phagocytic engulfment.
Topics: Animals; Biophysical Phenomena; Mechanotransduction, Cellular; Phagocytes; Phagocytosis
PubMed: 32698097
DOI: 10.1016/j.ceb.2020.05.011 -
Frontiers in Immunology 2020The spirochetal bacteria spp. are causative agents of leptospirosis, a globally neglected and reemerging zoonotic disease. Infection with these pathogens may lead to an... (Review)
Review
The spirochetal bacteria spp. are causative agents of leptospirosis, a globally neglected and reemerging zoonotic disease. Infection with these pathogens may lead to an acute and potentially fatal disease but also to chronic asymptomatic renal colonization. Both forms of disease demonstrate the ability of leptospires to evade the immune response of their hosts. In this review, we aim first to recapitulate the knowledge and explore the controversial data about the opsonization, recognition, intracellular survival, and killing of leptospires by scavenger cells, including platelets, neutrophils, macrophages, and dendritic cells. Second, we will summarize the known specificities of the recognition or escape of leptospire components (the so-called microbial-associated molecular patterns; MAMPs) by the pattern recognition receptors (PRRs) of the Toll-like and NOD-like families. These PRRs are expressed by phagocytes, and their stimulation by MAMPs triggers pro-inflammatory cytokine and chemokine production and bactericidal responses, such as antimicrobial peptide secretion and reactive oxygen species production. Finally, we will highlight recent studies suggesting that boosting or restoring phagocytic functions by treatments using agonists of the Toll-like or NOD receptors represents a novel prophylactic strategy and describe other potential therapeutic or vaccine strategies to combat leptospirosis.
Topics: Animals; Humans; Immune Evasion; Immunity, Innate; Leptospira; Leptospirosis; Macrophages; NLR Proteins; Neutrophils; Phagocytes; Phagocytosis; Toll-Like Receptors
PubMed: 33123147
DOI: 10.3389/fimmu.2020.571816 -
Frontiers in Immunology 2022Endogenous granulocyte-macrophage colony-stimulating factor (GM-CSF), identified by its ability to support differentiation of hematopoietic cells into several types of... (Review)
Review
INTRODUCTION
Endogenous granulocyte-macrophage colony-stimulating factor (GM-CSF), identified by its ability to support differentiation of hematopoietic cells into several types of myeloid cells, is now known to support maturation and maintain the metabolic capacity of mononuclear phagocytes including monocytes, macrophages, and dendritic cells. These cells sense and attack potential pathogens, present antigens to adaptive immune cells, and recruit other immune cells. Recombinant human (rhu) GM-CSF (e.g., sargramostim [glycosylated, yeast-derived rhu GM-CSF]) has immune modulating properties and can restore the normal function of mononuclear phagocytes rendered dysfunctional by deficient or insufficient endogenous GM-CSF.
METHODS
We reviewed the emerging biologic and cellular effects of GM-CSF. Experts in clinical disease areas caused by deficient or insufficient endogenous GM-CSF examined the role of GM-CSF in mononuclear phagocyte disorders including autoimmune pulmonary alveolar proteinosis (aPAP), diverse infections (including COVID-19), wound healing, and anti-cancer immune checkpoint inhibitor therapy.
RESULTS
We discuss emerging data for GM-CSF biology including the positive effects on mitochondrial function and cell metabolism, augmentation of phagocytosis and efferocytosis, and immune cell modulation. We further address how giving exogenous rhu GM-CSF may control or treat mononuclear phagocyte dysfunction disorders caused or exacerbated by GM-CSF deficiency or insufficiency. We discuss how rhu GM-CSF may augment the anti-cancer effects of immune checkpoint inhibitor immunotherapy as well as ameliorate immune-related adverse events.
DISCUSSION
We identify research gaps, opportunities, and the concept that rhu GM-CSF, by supporting and restoring the metabolic capacity and function of mononuclear phagocytes, can have significant therapeutic effects. rhu GM-CSF (e.g., sargramostim) might ameliorate multiple diseases of GM-CSF deficiency or insufficiency and address a high unmet medical need.
Topics: Humans; Granulocyte-Macrophage Colony-Stimulating Factor; Immune Checkpoint Inhibitors; COVID-19; Macrophages; Monocytes
PubMed: 36685591
DOI: 10.3389/fimmu.2022.1069444 -
Experimental Hematology Aug 2021The bone marrow (BM) contains a mosaic of niches specialized in supporting different maturity stages of hematopoietic stem and progenitor cells such as hematopoietic... (Review)
Review
The bone marrow (BM) contains a mosaic of niches specialized in supporting different maturity stages of hematopoietic stem and progenitor cells such as hematopoietic stem cells and myeloid, lymphoid, and erythroid progenitors. Recent advances in BM imaging and conditional gene knockout mice have revealed that niches are a complex network of cells of mesenchymal, endothelial, neuronal, and hematopoietic origins, together with local physicochemical parameters. Within these complex structures, phagocytes, such as neutrophils, macrophages, and dendritic cells, all of which are of hematopoietic origin, have been found to be important in regulating several niches in the BM, including hematopoietic stem cell niches, erythropoietic niches, and niches involved in endosteal bone formation. There is also increasing evidence that these macrophages have an important role in adapting hematopoiesis, erythropoiesis, and bone formation in response to inflammatory stressors and play a key part in maintaining the integrity and function of these. Likewise, there is also accumulating evidence that subsets of monocytes, macrophages, and other phagocytes contribute to the progression and response to treatment of several lymphoid malignancies such as multiple myeloma, Hodgkin lymphoma, and non-Hodgkin lymphoma, as well as lymphoblastic leukemia, and may also play a role in myelodysplastic syndrome and myeloproliferative neoplasms associated with Noonan syndrome and aplastic anemia. In this review, the potential functions of macrophages and other phagocytes in normal and pathologic niches are discussed, as are the challenges in studying BM and other tissue-resident macrophages at the molecular level.
Topics: Animals; Bone Marrow; Hematopoiesis; Hematopoietic Stem Cells; Humans; Lymphoma; Macrophages; Multiple Myeloma; Phagocytes; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 34298116
DOI: 10.1016/j.exphem.2021.07.001 -
JCI Insight Jul 2023The virulence of intracellular pathogens relies largely on the ability to survive and replicate within phagocytes but also on release and transfer into new host cells....
The virulence of intracellular pathogens relies largely on the ability to survive and replicate within phagocytes but also on release and transfer into new host cells. Such cell-to-cell transfer could represent a target for counteracting microbial pathogenesis. However, our understanding of the underlying cellular and molecular processes remains woefully insufficient. Using intravital 2-photon microscopy of caspase-3 activation in the Leishmania major-infected (L. major-infected) live skin, we showed increased apoptosis in cells infected by the parasite. Also, transfer of the parasite to new host cells occurred directly without a detectable extracellular state and was associated with concomitant uptake of cellular material from the original host cell. These in vivo findings were fully recapitulated in infections of isolated human phagocytes. Furthermore, we observed that high pathogen proliferation increased cell death in infected cells, and long-term residency within an infected host cell was only possible for slowly proliferating parasites. Our results therefore suggest that L. major drives its own dissemination to new phagocytes by inducing host cell death in a proliferation-dependent manner.
Topics: Leishmania major; Phagocytes; Apoptosis; Humans; Virulence; Mice, Inbred C57BL; Cells, Cultured; Mice; Animals
PubMed: 37310793
DOI: 10.1172/jci.insight.169020