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MBio Dec 2019Macrophages are well known for their phagocytic activity and their role in innate immune responses. Macrophages eat non-self particles, via a variety of mechanisms, and... (Review)
Review
Macrophages are well known for their phagocytic activity and their role in innate immune responses. Macrophages eat non-self particles, via a variety of mechanisms, and typically break down internalized cargo into small macromolecules. However, some pathogenic agents have the ability to evade this endosomal degradation through a nonlytic exocytosis process termed vomocytosis. This phenomenon has been most often studied for , a yeast that causes roughly 180,000 deaths per year, primarily in immunocompromised (e.g., human immunodeficiency virus [HIV]) patients. Existing dogma purports that vomocytosis involves distinctive cellular pathways and intracellular physicochemical cues in the host cell during phagosomal maturation. Moreover, it has been observed that the immunological state of the individual and macrophage phenotype affect vomocytosis outcomes. Here we compile the current knowledge on the factors (with respect to the phagocytic cell) that promote vomocytosis of from macrophages.
Topics: Animals; Calcium; Cryptococcus neoformans; Humans; Hydrogen-Ion Concentration; Macrophages; Mice; Phagocytosis; Phagosomes; Phenotype
PubMed: 31874916
DOI: 10.1128/mBio.02526-19 -
Seminars in Immunology Dec 2014Mycobacterium tuberculosis has succeeded in infecting one-third of the human race though inhibition or evasion of innate and adaptive immunity. The pathogen is a... (Review)
Review
Mycobacterium tuberculosis has succeeded in infecting one-third of the human race though inhibition or evasion of innate and adaptive immunity. The pathogen is a facultative intracellular parasite that uses the niche provided by mononuclear phagocytes for its advantage. Complex interactions determine whether the bacillus will or will not be delivered to acidified lysosomes, whether the host phagocyte will survive infection or die, and whether the timing and mode of cell death works to the advantage of the host or the pathogen. Here we discuss cell death and autophagy in TB. These fundamental processes of cell biology feature in all aspects of TB pathogenesis and may be exploited to the treatment or prevention of TB disease.
Topics: Apoptosis; Apoptosis Regulatory Proteins; Autophagy; Bacterial Proteins; Gene Expression Regulation; Humans; Immune Evasion; Immunity, Innate; Macrophages; Mycobacterium tuberculosis; Necrosis; Perforin; Phagosomes; Signal Transduction; Tuberculosis, Pulmonary
PubMed: 25453227
DOI: 10.1016/j.smim.2014.10.001 -
The European Respiratory Journal Mar 2021Sarcoidosis and tuberculosis are granulomatous pulmonary diseases characterised by heightened immune reactivity to antigens. We hypothesised that an unsupervised...
INTRODUCTION
Sarcoidosis and tuberculosis are granulomatous pulmonary diseases characterised by heightened immune reactivity to antigens. We hypothesised that an unsupervised analysis comparing the molecular characteristics of granulomas formed in response to antigens in patients with sarcoidosis or latent tuberculosis infection (LTBI) would provide novel insights into the pathogenesis of sarcoidosis.
METHODS
A genomic analysis identified differentially expressed genes in granuloma-like cell aggregates formed by sarcoidosis (n=12) or LTBI patients (n=5) in an established human granuloma model wherein peripheral blood mononuclear cells were exposed to antigens (beads coated with purified protein derivative) and cultured for 7 days. Pathway analysis of differentially expressed genes identified canonical pathways, most notably antigen processing and presentation phagolysosomes, as a prominent pathway in sarcoidosis granuloma formation. The phagolysosomal pathway promoted mechanistic target of rapamycin complex 1 (mTORc1)/STAT3 signal transduction. Thus, granuloma formation and related immune mediators were evaluated in the absence or presence of various pre-treatments known to prevent phagolysosome formation (chloroquine) or phagosome acidification (bafilomycin A1) or directly inhibit mTORc1 activation (rapamycin).
RESULTS
In keeping with genomic analyses indicating enhanced phagolysosomal activation and predicted mTORc1 signalling, it was determined that sarcoidosis granuloma formation and related inflammatory mediator release was dependent upon phagolysosome assembly and acidification and mTORc1/S6/STAT3 signal transduction.
CONCLUSIONS
Sarcoidosis granulomas exhibit enhanced and sustained intracellular antigen processing and presentation capacities, and related phagolysosome assembly and acidification are required to support mTORc1 signalling to promote sarcoidosis granuloma formation.
Topics: Granuloma; Humans; Leukocytes, Mononuclear; Phagosomes; Sarcoidosis; Signal Transduction; TOR Serine-Threonine Kinases
PubMed: 32943400
DOI: 10.1183/13993003.02695-2020 -
Current Opinion in Immunology Oct 2019Neutrophils are a crucial first line of defense against infection, migrating rapidly into tissues where they deploy granule components and toxic oxidants for efficient... (Review)
Review
Neutrophils are a crucial first line of defense against infection, migrating rapidly into tissues where they deploy granule components and toxic oxidants for efficient phagocytosis and microbe killing. Subsequent apoptosis and clearance of dying neutrophils are essential for control of infection and resolution of the inflammatory response. A subset of microbial pathogens survive exposure to neutrophils by manipulating phagocytosis, phagosome-granule fusion, oxidant production, and lifespan. Elucidating how they accomplish this unusual feat provides new insights into normal neutrophil function. In this review, we highlight recent discoveries about the ways in which neutrophils use cell-intrinsic mechanisms to control infection, and how these defenses are subverted by pathogens.
Topics: Animals; Biomarkers; Host-Pathogen Interactions; Humans; Immunity, Innate; Neutrophils; Oxidation-Reduction; Oxidative Stress; Phagocytosis; Phagosomes; Reactive Oxygen Species
PubMed: 31302568
DOI: 10.1016/j.coi.2019.05.004 -
Microbial Phagocytic Receptors and Their Potential Involvement in Cytokine Induction in Macrophages.Frontiers in Immunology 2021Phagocytosis is an essential process for the uptake of large (>0.5 µm) particulate matter including microbes and dying cells. Specialized cells in the body perform... (Review)
Review
Phagocytosis is an essential process for the uptake of large (>0.5 µm) particulate matter including microbes and dying cells. Specialized cells in the body perform phagocytosis which is enabled by cell surface receptors that recognize and bind target cells. Professional phagocytes play a prominent role in innate immunity and include macrophages, neutrophils and dendritic cells. These cells display a repertoire of phagocytic receptors that engage the target cells directly, or indirectly opsonins, to mediate binding and internalization of the target into a phagosome. Phagosome maturation then proceeds to cause destruction and recycling of the phagosome contents. Key subsequent events include antigen presentation and cytokine production to alert and recruit cells involved in the adaptive immune response. Bridging the innate and adaptive immunity, macrophages secrete a broad selection of inflammatory mediators to orchestrate the type and magnitude of an inflammatory response. This review will focus on cytokines produced by NF-κB signaling which is activated by extracellular ligands and serves a master regulator of the inflammatory response to microbes. Macrophages secrete pro-inflammatory cytokines including TNFα, IL1β, IL6, IL8 and IL12 which together increases vascular permeability and promotes recruitment of other immune cells. The major anti-inflammatory cytokines produced by macrophages include IL10 and TGFβ which act to suppress inflammatory gene expression in macrophages and other immune cells. Typically, macrophage cytokines are synthesized, trafficked intracellularly and released in response to activation of pattern recognition receptors (PRRs) or inflammasomes. Direct evidence linking the event of phagocytosis to cytokine production in macrophages is lacking. This review will focus on cytokine output after engagement of macrophage phagocytic receptors by particulate microbial targets. Microbial receptors include the PRRs: Toll-like receptors (TLRs), scavenger receptors (SRs), C-type lectin and the opsonic receptors. Our current understanding of how macrophage receptor stimulation impacts cytokine production is largely based on work utilizing soluble ligands that are destined for endocytosis. We will instead focus this review on research examining receptor ligation during uptake of particulate microbes and how this complex internalization process may influence inflammatory cytokine production in macrophages.
Topics: Animals; Antigens, Bacterial; Cytokines; Humans; Immunity, Innate; Macrophages; Mice; NF-kappa B p50 Subunit; Phagocytes; Phagocytosis; Phagosomes; Signal Transduction; Toll-Like Receptors
PubMed: 33995386
DOI: 10.3389/fimmu.2021.662063 -
Biomedical Journal Dec 2017In the normal non-diseased lung, various macrophage populations maintain homeostasis and sterility by ingesting and clearing inhaled particulates, pathogens and... (Review)
Review
In the normal non-diseased lung, various macrophage populations maintain homeostasis and sterility by ingesting and clearing inhaled particulates, pathogens and apoptotic cells from the local environment. This process of phagocytosis leads to the degradation of the internalized material, coordinated induction of gene expression, antigen presentation and cytokine production, implicating phagocytosis as a central regulator of innate immunity. Phagocytosis is extremely efficient and any perturbation of this function is deleterious. In inflammatory lung diseases such as chronic obstructive pulmonary disease (COPD), despite their increased numbers, macrophages demonstrate significantly reduced phagocytic capacity of bacteria and apoptotic cells. This defect could play a role in dysbiosis of the lung microbiome contributing to disease pathophysiology. In this review, we will discuss lung macrophages, describe phagocytosis and its related downstream processes and the reported phagocytosis defects in COPD. Finally, we will briefly examine current strategies that focus on restoring the phagocytic capabilities of lung macrophages that may have utility in COPD.
Topics: Humans; Lung; Macrophages, Alveolar; Phagocytosis; Phagosomes; Pulmonary Disease, Chronic Obstructive; Signal Transduction
PubMed: 29433833
DOI: 10.1016/j.bj.2017.09.004 -
Autophagy 2015Autophagy targets various intracellular components ranging from proteins and nucleic acids to organelles for their degradation in lysosomes or vacuoles. In selective... (Review)
Review
Autophagy targets various intracellular components ranging from proteins and nucleic acids to organelles for their degradation in lysosomes or vacuoles. In selective types of autophagy, receptor proteins play central roles in target selection. These proteins bind or localize to specific targets, and also interact with Atg8 family proteins on forming autophagosomal membranes, leading to the efficient sequestration of the targets by the membranes. Our recent study revealed that yeast cells actively degrade the endoplasmic reticulum (ER) and even part of the nucleus via selective autophagy under nitrogen-deprived conditions. We identified novel receptors, Atg39 and Atg40, specific to these pathways. Here, we summarize our findings on 'reticulophagy' (or 'ER-phagy') and 'nucleophagy', and discuss key issues that remain to be solved in future studies.
Topics: Animals; Autophagy; Cell Nucleus; Endoplasmic Reticulum; Humans; Lysosomes; Phagosomes; Saccharomyces cerevisiae Proteins
PubMed: 26566146
DOI: 10.1080/15548627.2015.1106665 -
International Journal of Molecular... Jun 2023Mouse guanylate-binding proteins (mGBPs) are recruited to various invasive pathogens, thereby conferring cell-autonomous immunity against these pathogens. However,...
Mouse guanylate-binding proteins (mGBPs) are recruited to various invasive pathogens, thereby conferring cell-autonomous immunity against these pathogens. However, whether and how human GBPs (hGBPs) target (Mtb) and (Lm) remains unclear. Here, we describe hGBPs association with intracellular Mtb and Lm, which was dependent on the ability of bacteria to induce disruption of phagosomal membranes. hGBP1 formed puncta structures which were recruited to ruptured endolysosomes. Furthermore, both GTP-binding and isoprenylation of hGBP1 were required for its puncta formation. hGBP1 was required for the recovery of endolysosomal integrity. In vitro lipid-binding assays demonstrated direct binding of hGBP1 to PI4P. Upon endolysosomal damage, hGBP1 was targeted to PI4P and PI(3,4)P2-positive endolysosomes in cells. Finally, live-cell imaging demonstrated that hGBP1 was recruited to damaged endolysosomes, and consequently mediated endolysosomal repair. In summary, we uncover a novel interferon-inducible mechanism in which hGBP1 contributes to the repair of damaged phagosomes/endolysosomes.
Topics: Humans; Animals; Mice; GTP-Binding Proteins; Phagosomes; Interferons; Endosomes
PubMed: 37298652
DOI: 10.3390/ijms24119701 -
Frontiers in Immunology 2021The rapid and efficient phagocytic clearance of apoptotic cells, termed efferocytosis, is a critical mechanism in the maintenance of tissue homeostasis. Removal of... (Review)
Review
The rapid and efficient phagocytic clearance of apoptotic cells, termed efferocytosis, is a critical mechanism in the maintenance of tissue homeostasis. Removal of apoptotic cells through efferocytosis prevents secondary necrosis and the resultant inflammation caused by the release of intracellular contents. The importance of efferocytosis in homeostasis is underscored by the large number of inflammatory and autoimmune disorders, including atherosclerosis and systemic lupus erythematosus, that are characterized by defective apoptotic cell clearance. Although mechanistically similar to the phagocytic clearance of pathogens, efferocytosis differs from phagocytosis in that it is immunologically silent and induces a tissue repair response. Efferocytes face unique challenges resulting from the internalization of apoptotic cells, including degradation of the apoptotic cell, dealing with the extra metabolic load imposed by the processing of apoptotic cell contents, and the coordination of an anti-inflammatory, pro-tissue repair response. This review will discuss recent advances in our understanding of the cellular response to apoptotic cell uptake, including trafficking of apoptotic cell cargo and antigen presentation, signaling and transcriptional events initiated by efferocytosis, the coordination of an anti-inflammatory response and tissue repair, unique cellular metabolic responses and the role of efferocytosis in host defense. A better understanding of how efferocytic cells respond to apoptotic cell uptake will be critical in unraveling the complex connections between apoptotic cell removal and inflammation resolution and maintenance of tissue homeostasis.
Topics: Antigen Presentation; Apoptosis; Gene Expression Regulation; Homeostasis; Humans; Inflammation; Phagocytes; Phagocytosis; Phagosomes; Signal Transduction
PubMed: 33959122
DOI: 10.3389/fimmu.2021.631714 -
International Journal of Molecular... Feb 2023Phagocytosis is one of the most polarised of all cellular activities. Both the stimulus (the target for phagocytosis) and the response (its internalisation) are focussed... (Review)
Review
Phagocytosis is one of the most polarised of all cellular activities. Both the stimulus (the target for phagocytosis) and the response (its internalisation) are focussed at just one part of the cell. At the locus, and this locus alone, pseudopodia form a phagocytic cup around the particle, the cytoskeleton is rearranged, the plasma membrane is reorganised, and a new internal organelle, the phagosome, is formed. The effect of signals from the stimulus must, thus, both be complex and yet be restricted in space and time to enable an effective focussed response. While many aspects of phagocytosis are being uncovered, the mechanism for the restriction of signalling or the effects of signalling remains obscure. In this review, the details of the problem of restricting chemical intracellular signalling are presented, with a focus on diffusion into the cytosol and of signalling lipids along the plasma membrane. The possible ways in which simple diffusion is overcome so that the restriction of signalling and effective phagocytosis can be achieved are discussed in the light of recent advances in imaging, biophysics, and cell biochemistry which together are providing new insights into this area.
Topics: Phagocytosis; Phagosomes; Pseudopodia; Cytoskeleton; Cytosol
PubMed: 36769146
DOI: 10.3390/ijms24032825