-
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 -
The FEBS Journal Feb 2016The fungal pathogen Histoplasma capsulatum causes respiratory and disseminated disease, even in immunocompetent hosts. In contrast to opportunistic pathogens, which are... (Review)
Review
The fungal pathogen Histoplasma capsulatum causes respiratory and disseminated disease, even in immunocompetent hosts. In contrast to opportunistic pathogens, which are readily controlled by phagocytic cells, H. capsulatum yeasts are able to infect macrophages, survive antimicrobial defenses, and proliferate as an intracellular pathogen. In this review, we discuss some of the molecular mechanisms that enable H. capsulatum yeasts to overcome obstacles to intracellular pathogenesis. H. capsulatum yeasts gain refuge from extracellular obstacles such as antimicrobial lung surfactant proteins by engaging the β-integrin family of phagocytic receptors to promote entry into macrophages. In addition, H. capsulatum yeasts conceal immunostimulatory β-glucans to avoid triggering signaling receptors such as the β-glucan receptor Dectin-1. H. capsulatum yeasts counteract phagocyte-produced reactive oxygen species by expression of oxidative stress defense enzymes including an extracellular superoxide dismutase and an extracellular catalase. Within the phagosome, H. capsulatum yeasts block phagosome acidification, acquire essential metals such as iron and zinc, and utilize de novo biosynthesis pathways to overcome nutritional limitations. These mechanisms explain how H. capsulatum yeasts avoid and negate macrophage defense strategies and establish a hospitable intracellular niche, making H. capsulatum a successful intracellular pathogen of macrophages.
Topics: Catalase; Histoplasma; Humans; Macrophages; Reactive Oxygen Species; Superoxide Dismutase
PubMed: 26235362
DOI: 10.1111/febs.13389 -
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 -
Journal of Immunology (Baltimore, Md. :... Feb 2017Since the pioneering work of Elie Metchnikoff and the discovery of cellular immunity, the phagocytic clearance of cellular debris has been considered an integral... (Review)
Review
Since the pioneering work of Elie Metchnikoff and the discovery of cellular immunity, the phagocytic clearance of cellular debris has been considered an integral component of resolving inflammation and restoring function of damaged and infected tissues. We now know that the phagocytic clearance of dying cells (efferocytosis), particularly by macrophages and other immune phagocytes, has profound consequences on innate and adaptive immune responses in inflamed tissues. These immunomodulatory effects result from an array of molecular signaling events between macrophages, dying cells, and other tissue-resident cells. In recent years, many of these molecular pathways have been identified and studied in the context of tissue inflammation, helping us better understand the relationship between efferocytosis and inflammation. We review specific types of efferocytosis-related signals that can impact macrophage immune responses and discuss their relevance to inflammation-related diseases.
Topics: Animals; Apoptosis; Cells, Cultured; Humans; Immunity, Innate; Inflammation; Macrophages; Mice; Phagocytes; Phagocytosis; Signal Transduction
PubMed: 28167649
DOI: 10.4049/jimmunol.1601520 -
Seminars in Immunopathology Jul 2016Innate immunity normally provides excellent defence against invading microorganisms. Acute inflammation is a form of innate immune defence and represents one of the... (Review)
Review
Innate immunity normally provides excellent defence against invading microorganisms. Acute inflammation is a form of innate immune defence and represents one of the primary responses to injury, infection and irritation, largely mediated by granulocyte effector cells such as neutrophils and eosinophils. Failure to remove an inflammatory stimulus (often resulting in failed resolution of inflammation) can lead to chronic inflammation resulting in tissue injury caused by high numbers of infiltrating activated granulocytes. Successful resolution of inflammation is dependent upon the removal of these cells. Under normal physiological conditions, apoptosis (programmed cell death) precedes phagocytic recognition and clearance of these cells by, for example, macrophages, dendritic and epithelial cells (a process known as efferocytosis). Inflammation contributes to immune defence within the respiratory mucosa (responsible for gas exchange) because lung epithelia are continuously exposed to a multiplicity of airborne pathogens, allergens and foreign particles. Failure to resolve inflammation within the respiratory mucosa is a major contributor of numerous lung diseases. This review will summarise the major mechanisms regulating lung inflammation, including key cellular interplays such as apoptotic cell clearance by alveolar macrophages and macrophage/neutrophil/epithelial cell interactions. The different acute and chronic inflammatory disease states caused by dysregulated/impaired resolution of lung inflammation will be discussed. Furthermore, the resolution of lung inflammation during neutrophil/eosinophil-dominant lung injury or enhanced resolution driven via pharmacological manipulation will also be considered.
Topics: Animals; Apoptosis; Cell Death; Cytokines; Humans; Immune System; Immunity, Innate; Inflammation; Inflammation Mediators; Lipid Metabolism; Lung Diseases; Phagocytes; Phagocytosis; Respiratory Mucosa
PubMed: 27116944
DOI: 10.1007/s00281-016-0560-6 -
International Journal of Molecular... Dec 2022The mononuclear phagocytic system (MPS) is the primary innate immune cell group in male reproductive tissues, maintaining the balance of pro-inflammatory and immune... (Review)
Review
The mononuclear phagocytic system (MPS) is the primary innate immune cell group in male reproductive tissues, maintaining the balance of pro-inflammatory and immune tolerance. This article aims to outline the role of mononuclear macrophages in the immune balance of the testes and epididymis, and to understand the inner immune regulation mechanism. A review of pertinent publications was performed using the PubMed and Google Scholar databases on all articles published prior to January 2021. Search terms were based on the following keywords: 'MPS', 'mononuclear phagocytes', 'testes', 'epididymis', 'macrophage', 'Mφ', 'dendritic cell', 'DC', 'TLR', 'immune', 'inflammation', and 'polarization'. Additionally, reference lists of primary and review articles were reviewed for other publications of relevance. This review concluded that MPS exhibits a precise balance in the male reproductive system. In the testes, MPS cells are mainly suppressed subtypes (M2 and cDC2) under physiological conditions, which maintain the local immune tolerance. Under pathological conditions, MPS cells will transform into M1 and cDC1, producing various cytokines, and will activate T cell specific immunity as defense to foreign pathogens or self-antigens. In the epididymis, MPS cells vary in the different segments, which express immune tolerance in the caput and pro-inflammatory condition in the cauda. Collectively, MPS is the control point for maintaining the immune tolerance of the testes and epididymis as well as for eliminating pathogens.
Topics: Male; Humans; Macrophages; Mononuclear Phagocyte System; Epididymis; Testis; T-Lymphocytes
PubMed: 36613494
DOI: 10.3390/ijms24010053 -
Immunological Investigations Oct 2020Phosphatidylserine (PS) is a naturally occurring anionic phospholipid that is primarily located in the inner leaflet of eukaryotic cell membranes. The role of PS during... (Review)
Review
Phosphatidylserine (PS) is a naturally occurring anionic phospholipid that is primarily located in the inner leaflet of eukaryotic cell membranes. The role of PS during apoptosis is one of the most studied biological functions of PS. Externalization of PS during apoptosis mediates an "eat me" signal for phagocytic uptake, leading to clearance of apoptotic cells and thus maintain self-tolerance by immunological ignorance. However, an emerging view is that PS exposure-mediated cellular uptake is not an immunologically silent event, but rather promoting an active tolerance towards self and foreign proteins. This biological property of PS has been exploited by parasites and viruses in order to evade immune surveillance of the host immune system. Further, this novel immune regulatory property of PS that results in tolerance induction can be harnessed for clinical applications, such as to treat autoimmune conditions and to reduce immunogenicity of therapeutic proteins. This review attempts to provide an overview of the biological functions of PS in the immune response and its potential therapeutic applications.
Topics: Animals; Apoptosis; Drug Design; Drug Development; Humans; Immunotherapy; Molecular Structure; Nanoparticles; Phagocytes; Phagocytosis; Phosphatidylserines; Theranostic Nanomedicine
PubMed: 32204629
DOI: 10.1080/08820139.2020.1738456