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FEMS Microbiology Reviews May 2010Microorganisms have developed several mechanisms to modulate the host immune system to increase their survival and propagation in the host. Their presence in the host is... (Review)
Review
Microorganisms have developed several mechanisms to modulate the host immune system to increase their survival and propagation in the host. Their presence in the host is not only revealed by self-produced peptides but also through host-derived chemokines and active complement fragments. These so-called chemoattractants are recognized by G protein-coupled receptors (GPCRs) expressed on leukocyte cell membranes. Activation of GPCRs triggers leukocyte activation and guides their recruitment to the site of infection. Therefore, GPCRs play a central role in leukocyte trafficking leading to microbial clearance. It is therefore not surprising that microorganisms are able to sabotage this arm of the immune response. Different microorganisms have evolved a variety of tactics to modulate GPCR activation. Here, we review the mechanisms and proteins used by major human pathogens and less virulent microorganisms that affect GPCR signaling. While viruses generally produce receptor and chemoattractant mimics, parasites and bacteria such as Staphylococcus aureus, Streptococcus pyogenes, Porphyromonas gingivalis, and Bordetella pertussis secrete proteins that affect receptor signaling, directly antagonize receptors, cleave stimuli, and even prevent stimulus generation. As the large arsenal of GPCR modulators aids prolonged microbial persistence in the host, their study provides us a better understanding of microbial pathogenesis.
Topics: Animals; Cell Movement; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Immune Evasion; Phagocytes; Virulence; Virulence Factors
PubMed: 20059549
DOI: 10.1111/j.1574-6976.2009.00202.x -
Blood Aug 2008The production and deployment of phagocytes are central functions of the hematopoietic system. In the 1950s, radioisotopic studies demonstrated the high production rate... (Review)
Review
The production and deployment of phagocytes are central functions of the hematopoietic system. In the 1950s, radioisotopic studies demonstrated the high production rate and short lifespan of neutrophils and allowed researchers to follow the monocytes as they moved from the marrow through the blood to become tissue macrophages, histiocytes, and dendritic cells. Subsequently, the discovery of the colony-stimulating factors greatly improved understanding the regulation of phagocyte production. The discovery of the microbicidal myeloperoxidase-H2O2-halide system and the importance of NADPH oxidase to the generation of H2O2 also stimulated intense interest in phagocyte disorders. More recent research has focused on membrane receptors and the dynamics of the responses of phagocytes to external factors including immunoglobulins, complement proteins, cytokines, chemokines, integrins, and selectins. Phagocytes express toll-like receptors that aid in the clearance of a wide range of microbial pathogens and their products. Phagocytes are also important sources of pro- and anti-inflammatory cytokines, thus participating in host defenses through a variety of mechanisms. Over the last 50 years, many genetic and molecular disorders of phagocytes have been identified, leading to improved diagnosis and treatment of conditions which predispose patients to the risk of recurrent fevers and infectious diseases.
Topics: Immunologic Deficiency Syndromes; Monocytes; Neutrophils; Phagocytes; Receptors, Cell Surface
PubMed: 18684880
DOI: 10.1182/blood-2007-12-077917 -
Immunological Reviews Sep 2016One of the most fascinating and exciting periods in my scientific career entailed dissecting the symbiotic relationship between two membrane transporters, the... (Review)
Review
One of the most fascinating and exciting periods in my scientific career entailed dissecting the symbiotic relationship between two membrane transporters, the Nicotinamide adenine dinucleotide phosphate reduced form (NADPH) oxidase complex and voltage-gated proton channels (HV 1). By the time I entered this field, there had already been substantial progress toward understanding NADPH oxidase, but HV 1 were known only to a tiny handful of cognoscenti around the world. Having identified the first proton currents in mammalian cells in 1991, I needed to find a clear function for these molecules if the work was to become fundable. The then-recent discoveries of Henderson, Chappell, and colleagues in 1987-1988 that led them to hypothesize interactions of both molecules during the respiratory burst of phagocytes provided an excellent opportunity. In a nutshell, both transporters function by moving electrical charge across the membrane: NADPH oxidase moves electrons and HV 1 moves protons. The consequences of electrogenic NADPH oxidase activity on both membrane potential and pH strongly self-limit this enzyme. Fortunately, both consequences specifically activate HV 1, and HV 1 activity counteracts both consequences, a kind of yin-yang relationship. Notwithstanding a decade starting in 1995 when many believed the opposite, these are two separate molecules that function independently despite their being functionally interdependent in phagocytes. The relationship between NADPH oxidase and HV 1 has become a paradigm that somewhat surprisingly has now extended well beyond the phagocyte NADPH oxidase - an industrial strength producer of reactive oxygen species (ROS) - to myriad other cells that produce orders of magnitude less ROS for signaling purposes. These cells with their seven NADPH oxidase (NOX) isoforms provide a vast realm of mechanistic obscurity that will occupy future studies for years to come.
Topics: Animals; Humans; Ion Channels; Membrane Potentials; NADPH Oxidases; Neutrophils; Phagocytes; Reactive Oxygen Species; Respiratory Burst; Signal Transduction
PubMed: 27558336
DOI: 10.1111/imr.12437 -
Biochemical Society Transactions Apr 2021Although millions of cells in the human body will undergo programmed cell death each day, dying cells are rarely detected under homeostatic settings in vivo. The swift... (Review)
Review
Although millions of cells in the human body will undergo programmed cell death each day, dying cells are rarely detected under homeostatic settings in vivo. The swift removal of dying cells is due to the rapid recruitment of phagocytes to the site of cell death which then recognise and engulf the dying cell. Apoptotic cell clearance - the engulfment of apoptotic cells by phagocytes - is a well-defined process governed by a series of molecular factors including 'find-me', 'eat-me', 'don't eat-me' and 'good-bye' signals. However, in recent years with the rapid expansion of the cell death field, the removal of other necrotic-like cell types has drawn much attention. Depending on the type of death, dying cells employ different mechanisms to facilitate engulfment and elicit varying functional impacts on the phagocyte, from wound healing responses to inflammatory cytokine secretion. Nevertheless, despite the mechanism of death, the clearance of dying cells is a fundamental process required to prevent the uncontrolled release of pro-inflammatory mediators and inflammatory disease. This mini-review summarises the current understandings of: (i) apoptotic, necrotic, necroptotic and pyroptotic cell clearance; (ii) the functional consequences of dying cell engulfment and; (iii) the outstanding questions in the field.
Topics: Animals; Apoptosis; Cytokines; Humans; Models, Biological; Necroptosis; Necrosis; Phagocytes; Phagocytosis; Pyroptosis; Signal Transduction
PubMed: 33843978
DOI: 10.1042/BST20200696 -
The Journal of Investigative Dermatology Dec 1979
Review
Topics: Anti-Bacterial Agents; Chemotactic Factors; Chemotaxis; Chemotaxis, Leukocyte; Colchicine; Glucocorticoids; Humans; Neutrophils; Phagocyte Bactericidal Dysfunction; Phagocytes
PubMed: 390059
DOI: 10.1111/1523-1747.ep12541374 -
Cellular and Molecular Life Sciences :... Jul 2008Src-family kinases (SFKs) regulate different granulocyte and monocyte/macrophage responses. Accumulating evidence suggests that members of this family are implicated in... (Review)
Review
Src-family kinases (SFKs) regulate different granulocyte and monocyte/macrophage responses. Accumulating evidence suggests that members of this family are implicated in signal transduction pathways regulating phagocytic cell migration and recruitment into inflammatory sites. Macrophages with a genetic deficiency of SFKs display marked alterations in cytoskeleton dynamics, polarization and migration. This same phenotype is found in cells with either a lack of SFK substrates and/or interacting proteins such as Pyk2/FAK, c-Cbl and p190RhoGAP. Notably, SFKs and their downstream targets also regulate monocyte recruitment into inflammatory sites. Depending on the type of assay used, neutrophil migration in vitro may be either dependent on or independent of SFKs. Also neutrophil recruitment in in vivo models of inflammation may be regulated differently by SFKs depending on the tissue involved. In this review we will discuss possible mechanisms by which SFKs may regulate phagocytic cell migratory abilities.
Topics: Animals; Cell Movement; Chemotaxis; Humans; Inflammation; Integrins; Macrophages; Models, Biological; Neutrophils; Phagocytes; Signal Transduction; ZAP-70 Protein-Tyrosine Kinase; src-Family Kinases
PubMed: 18385944
DOI: 10.1007/s00018-008-8005-6 -
Biochemical Pharmacology Sep 2010Phagocytes such as neutrophils, monocytes and macrophages play an essential role in host defenses against pathogens. To kill these pathogens, phagocytes produce and... (Review)
Review
Phagocytes such as neutrophils, monocytes and macrophages play an essential role in host defenses against pathogens. To kill these pathogens, phagocytes produce and release large quantities of antimicrobial molecules such as reactive oxygen species (ROS), microbicidal peptides, and proteases. The enzyme responsible for ROS generation is called NADPH oxidase, or respiratory burst oxidase, and is composed of six proteins: gp91phox, p22phox, p47phox, p67phox, p40phox and Rac1/2. The vital importance of this enzyme in host defenses is illustrated by a genetic disorder called chronic granulomatous disease (CGD), in which the phagocyte NADPH oxidase is dysfunctional, leading to life-threatening recurrent bacterial and fungal infections. However, excessive NADPH oxidase activation and ROS over-production can damage surrounding tissues and participate in exaggerated inflammatory processes. As ROS production is believed to be involved in several inflammatory diseases, specific phagocyte NADPH oxidase inhibitors might have therapeutic value. In this commentary, we summarize the structure and activation of the phagocyte NADPH oxidase, and describe pharmacological inhibitors of this enzyme, with particular emphasis on peptide-based inhibitors derived from gp91phox, p22phox and p47phox.
Topics: Amino Acid Sequence; Animals; Humans; Molecular Sequence Data; NADPH Oxidases; Peptide Mapping; Peptides; Phagocytes
PubMed: 20510204
DOI: 10.1016/j.bcp.2010.05.020 -
Journal of Advanced Research Jul 2021Even though exosome-based therapy has been shown to be able to control the progression of different pathologies, the data revealed by pharmacokinetic studies warn of the... (Review)
Review
BACKGROUND
Even though exosome-based therapy has been shown to be able to control the progression of different pathologies, the data revealed by pharmacokinetic studies warn of the low residence time of exogenous exosomes in circulation that can hinder the clinical translation of therapeutic exosomes. The macrophages related to the organs of the mononuclear phagocytic system are responsible primarily for the rapid clearance and retention of exosomes, which strongly limits the amount of exosomal particles available to reach the target tissue, accumulate in it and release with high efficiency its therapeutic cargo in acceptor target cells to exert the desired biological effect.
AIM OF REVIEW
Endowing exosomes with surface modifications to evade the immune system is a plausible strategy to contribute to the suppression of exosomal clearance and increase the efficiency of their targeted content delivery. Here, we summarize the current evidence about the mechanisms underlying the recognition and sequestration of therapeutic exosomes by phagocytic cells. Also, we propose different strategies to generate 'invisible' exosomes for the immune system, through the incorporation of different anti-phagocytic molecules on the exosomes' surface that allow increasing the circulating half-life of therapeutic exosomes with the purpose to increase their bioavailability to reach the target tissue, transfer their therapeutic molecular cargo and improve their efficacy profile.
KEY SCIENTIFIC CONCEPTS OF REVIEW
Macrophage-mediated phagocytosis are the main responsible behind the short half-life in circulation of systemically injected exosomes, hindering their therapeutic effect. Exosomes 'Camouflage Cloak' strategy using antiphagocytic molecules can contribute to the inhibition of exosomal clearance, hence, increasing the on-target effect. Some candidate molecules that could exert an antiphagocytic role are CD47, CD24, CD44, CD31, β2M, PD-L1, App1, and DHMEQ. Pre- and post-isolation methods for exosome engineering are compatible with the loading of therapeutic cargo and the expression of antiphagocytic surface molecules.
Topics: B7-H1 Antigen; Biological Availability; Biological Mimicry; CD24 Antigen; CD47 Antigen; Drug Delivery Systems; Exosomes; Humans; Hyaluronan Receptors; Immune System; Macrophages; Mononuclear Phagocyte System; Phagocytes; Phagocytosis
PubMed: 34194832
DOI: 10.1016/j.jare.2021.01.001 -
Frontiers in Immunology 2020Tissue-resident phagocytes are responsible for the routine binding, engulfment, and resolution of their meals. Such populations of cells express appropriate surface... (Review)
Review
Tissue-resident phagocytes are responsible for the routine binding, engulfment, and resolution of their meals. Such populations of cells express appropriate surface receptors that are tailored to recognize the phagocytic targets of their niche and initiate the actin polymerization that drives internalization. Tissue-resident phagocytes also harbor enzymes and transporters along the endocytic pathway that orchestrate the resolution of ingested macromolecules from the phagolysosome. Solutes fluxed from the endocytic pathway and into the cytosol can then be reutilized by the phagocyte or exported for their use by neighboring cells. Such a fundamental metabolic coupling between resident phagocytes and the tissue in which they reside is well-emphasized in the case of retinal pigment epithelial (RPE) cells; specialized phagocytes that are responsible for the turnover of photoreceptor outer segments (POS). Photoreceptors are prone to photo-oxidative damage and their long-term health depends enormously on the disposal of aged portions of the outer segment. The phagocytosis of the POS by the RPE is the sole means of this turnover and clearance. RPE are themselves mitotically quiescent and therefore must resolve the ingested material to prevent their toxic accumulation in the lysosome that otherwise leads to retinal disorders. Here we describe the sequence of events underlying the healthy turnover of photoreceptors by the RPE with an emphasis on the signaling that ensures the phagocytosis of the distal POS and on the transport of solutes from the phagosome that supersedes its resolution. While other systems may utilize different receptors and transporters, the biophysical and metabolic manifestations of such events are expected to apply to all tissue-resident phagocytes that perform regular phagocytic programs.
Topics: Animals; Epithelial Cells; Humans; Phagocytes; Phagocytosis; Retinal Photoreceptor Cell Outer Segment; Retinal Pigment Epithelium; Signal Transduction
PubMed: 33281830
DOI: 10.3389/fimmu.2020.604205 -
Cell Dec 2011Billions of cells die via apoptosis every day and are swiftly removed. When a phagocyte engulfs an apoptotic cell, it essentially doubles its cellular contents, raising... (Review)
Review
Billions of cells die via apoptosis every day and are swiftly removed. When a phagocyte engulfs an apoptotic cell, it essentially doubles its cellular contents, raising the question of how a phagocyte may manage the excess metabolic load. This Minireview discusses phagocyte cellular metabolism, the digestion of the ingested apoptotic cell, and the impact of these processes on engulfment.
Topics: Animals; Apoptosis; Cell Physiological Phenomena; Glucose; Humans; Lipid Metabolism; Phagocytes; Phagocytosis
PubMed: 22196723
DOI: 10.1016/j.cell.2011.12.006