-
EMBO Reports Jun 2021Timely removal of dying or pathogenic cells by phagocytes is essential to maintaining host homeostasis. Phagocytes execute the clearance process with high fidelity while... (Review)
Review
Timely removal of dying or pathogenic cells by phagocytes is essential to maintaining host homeostasis. Phagocytes execute the clearance process with high fidelity while sparing healthy neighboring cells, and this process is at least partially regulated by the balance of "eat-me" and "don't-eat-me" signals expressed on the surface of host cells. Upon contact, eat-me signals activate "pro-phagocytic" receptors expressed on the phagocyte membrane and signal to promote phagocytosis. Conversely, don't-eat-me signals engage "anti-phagocytic" receptors to suppress phagocytosis. We review the current knowledge of don't-eat-me signaling in normal physiology and disease contexts where aberrant don't-eat-me signaling contributes to pathology.
Topics: Apoptosis; Biological Phenomena; Phagocytes; Phagocytosis; Signal Transduction
PubMed: 34041845
DOI: 10.15252/embr.202152564 -
Experimental & Molecular Medicine Apr 2009Phagocytes such as neutrophils play a vital role in host defense against microbial pathogens. The anti-microbial function of neutrophils is based on the production of... (Review)
Review
Phagocytes such as neutrophils play a vital role in host defense against microbial pathogens. The anti-microbial function of neutrophils is based on the production of superoxide anion (O2 -), which generates other microbicidal reactive oxygen species (ROS) and release of antimicrobial peptides and proteins. The enzyme responsible for O2 - production is called the NADPH oxidase or respiratory burst oxidase. This multicomponent enzyme system is composed of two trans- membrane proteins (p22phox and gp91phox, also called NOX2, which together form the cytochrome b558) and four cytosolic proteins (p47phox, p67phox, p40phox and a GTPase Rac1 or Rac2), which assemble at membrane sites upon cell activation. NADPH oxidase activation in phagocytes can be induced by a large number of soluble and particulate agents. This process is dependent on the phosphorylation of the cytosolic protein p47phox. p47phox is a 390 amino acids protein with several functional domains: one phox homology (PX) domain, two src homology 3 (SH3) domains, an auto-inhibitory region (AIR), a proline rich domain (PRR) and has several phosphorylated sites located between Ser303 and Ser379. In this review, we will describe the structure of p47phox, its phosphorylation and discuss how these events regulate NADPH oxidase activation.
Topics: Disease; Enzyme Activation; Humans; Membrane Glycoproteins; NADPH Oxidase 2; NADPH Oxidases; Phagocytes; Phosphorylation; Protein Conformation
PubMed: 19372727
DOI: 10.3858/emm.2009.41.4.058 -
Journal of Immunology (Baltimore, Md. :... Jul 2021Alcohol use disorders (AUD) increase susceptibility to respiratory infections by 2- to 4-fold in part because of impaired alveolar macrophage (AM) immune function....
Alcohol use disorders (AUD) increase susceptibility to respiratory infections by 2- to 4-fold in part because of impaired alveolar macrophage (AM) immune function. Alcohol causes AM oxidative stress, diminishing AM phagocytic capacity and clearance of microbes from the alveolar space. Alcohol increases AM NADPH oxidases (Noxes), primary sources of AM oxidative stress, and reduces peroxisome proliferator-activated receptor γ (PPARγ) expression, a critical regulator of AM immune function. To investigate the underlying mechanisms of these alcohol-induced AM derangements, we hypothesized that alcohol stimulates CCAAT/enhancer-binding protein β (C/EBPβ) to suppress Nox-related microRNAs (miRs), thereby enhancing AM Nox expression, oxidative stress, and phagocytic dysfunction. Furthermore, we postulated that pharmacologic PPARγ activation with pioglitazone would inhibit C/EBPβ and attenuate alcohol-induced AM dysfunction. AM isolated from human AUD subjects or otherwise healthy control subjects were examined. Compared with control AM, alcohol activated AM C/EBPβ, decreased Nox1-related miR-1264 and Nox2-related miR-107, and increased Nox1, Nox2, and Nox4 expression and activity. These alcohol-induced AM derangements were abrogated by inhibition of C/EBPβ, overexpression of miR-1264 or miR-107, or pioglitazone treatment. These findings define novel molecular mechanisms of alcohol-induced AM dysfunction mediated by C/EBPβ and Nox-related miRs that are amenable to therapeutic targeting with PPARγ ligands. These results demonstrate that PPARγ ligands provide a novel and rapidly translatable strategy to mitigate susceptibility to respiratory infections and related morbidity in individuals with AUD.
Topics: Alcoholism; CCAAT-Enhancer-Binding Protein-beta; Cell Line; Ethanol; Humans; Lung; Macrophages, Alveolar; Male; NADPH Oxidases; Oxidative Stress; PPAR gamma; Phagocytes; Pioglitazone
PubMed: 34193599
DOI: 10.4049/jimmunol.2000565 -
The American Journal of Pathology Sep 1977Tentative conclusions concerning the role of recognition and ingestion of microorganisms by phagocytes in host defense and the consequences of disorders of phagocytosis... (Review)
Review
Tentative conclusions concerning the role of recognition and ingestion of microorganisms by phagocytes in host defense and the consequences of disorders of phagocytosis can be derived by correlating a) knowledge about recognition and ingestion derived from studies in vitro, b) investigations of the clearance of particulate matter from the circulation of animals and man, and c) analyses of the behavior of phagocytes in patients susceptible to recurrent pyogenic infections. Deficiency of the major serum recognition-conferring (immunoglobulins and complement proteins that deposit a fragment of C3 on microbes) prevents the optimal clearance of virulent encapsulated pathogens by fixed mononuclear phagocytes. Confrontation of phagocytes with particulate matter appearing in pathologic states (viruses, immune complexes, damaged erythrocytes in sickle cell anemia and other hemoglobinopathies) diverts them from their normal task of clearing opsonized encapsulated microorganisms. Corticosteroids impair the phagocytic capacity by an unknown mechanism. Major impediments to progress in this field are inadequate assays for phagocytosis and the difficulty in measuring phagocytosis in the intact organism.
Topics: Anemia, Sickle Cell; Animals; Antigen-Antibody Complex; Complement C3; Dysgammaglobulinemia; Humans; Immunologic Deficiency Syndromes; Immunologic Memory; Monocytes; Opsonin Proteins; Phagocyte Bactericidal Dysfunction; Phagocytes; Phagocytosis; Virulence
PubMed: 329684
DOI: No ID Found -
Seminars in Cell & Developmental Biology May 2019Phagocytosis is an essential step in the innate immune response to invasive fungal infections. This process is carried out by a proverbial "village" of professional... (Review)
Review
Phagocytosis is an essential step in the innate immune response to invasive fungal infections. This process is carried out by a proverbial "village" of professional phagocytic cells, which have evolved efficient machinery to recognize and ingest pathogens, namely macrophages, neutrophils and dendritic cells. These innate immune cells drive early cytokine production, fungicidal activity, antigen presentation and activation of the adaptive immune system. Despite the development of antifungal agents with potent activity, the biological activity of professional phagocytic innate immune cells has proven indispensable in protecting a host from invasive fungal infections. Additionally, an emerging body of evidence suggests non-professional phagocytes, such as airway epithelial cells, carry out phagocytosis and may play a critical role in the elimination of fungal pathogens. Here, we review recent advances of phagocytosis by both professional and non-professional phagocytes in response to fungal pathogens, with a focus on invasive aspergillosis as a model disease.
Topics: Adaptive Immunity; Antigen Presentation; Cytokines; Dendritic Cells; Fungi; Humans; Immunity, Innate; Invasive Fungal Infections; Macrophages; Neutrophils; Phagocytes; Phagocytosis
PubMed: 29727727
DOI: 10.1016/j.semcdb.2018.04.008 -
Journal of Innate Immunity 2009The interactions between Mycobacterium tuberculosis and host phagocytes such as macrophages and dendritic cells are central to both immunity and pathogenesis. Many... (Review)
Review
The interactions between Mycobacterium tuberculosis and host phagocytes such as macrophages and dendritic cells are central to both immunity and pathogenesis. Many receptors have been implicated in recognition and binding of M. tuberculosis such as the mannose receptor, dendritic-cell-specific intercellular adhesion molecule-3 grabbing nonintegrin, dectin-1 and complement receptor 3 as well as Toll-like receptors, scavenger receptors and CD14. While in vitro studies have demonstrated clear roles for particular receptor(s), in vivo work in receptor-deficient animals often revealed only a minor, or no role, in infection with M. tuberculosis. The initial encounter of phagocytic cells with myco- bacteria appears to be complex and depends on various parameters. It seems likely that infection with M. tuberculosis does not occur via a single receptor-mediated pathway. Rather, multiple receptors play different roles in M. tuberculosis infection, and the overall effect depends on the expression and availability of a particular receptor on a particular cell type and its triggered downstream responses. Moreover, the role of membrane cholesterol for M. tuberculosis interactions with phagocytes adds to the complexity of mycobacterial recognition and response. This review summarizes current knowledge on non-opsonic receptors involved in binding of mycobacteria and discusses the contribution of individual receptors to the recognition process.
Topics: Dendritic Cells; Humans; Immunity, Innate; Macrophages; Mycobacterium tuberculosis; Phagocytes; Receptors, Immunologic; Tuberculosis
PubMed: 20375581
DOI: 10.1159/000173703 -
The Journal of Allergy and Clinical... Feb 2015Deficient production of reactive oxygen species (ROS) by the phagocyte nicotinamide adenine dinucleotide (NADPH) oxidase in patients with chronic granulomatous disease...
BACKGROUND
Deficient production of reactive oxygen species (ROS) by the phagocyte nicotinamide adenine dinucleotide (NADPH) oxidase in patients with chronic granulomatous disease (CGD) results in susceptibility to certain pathogens secondary to impaired oxidative killing and mobilization of other phagocyte defenses. Peroxisome proliferator-activated receptor (PPAR) γ agonists, including pioglitazone, approved for type 2 diabetes therapy alter cellular metabolism and can heighten ROS production. It was hypothesized that pioglitazone treatment of gp91(phox-/-) mice, a murine model of human CGD, would enhance phagocyte oxidant production and killing of Staphylococcus aureus, a significant pathogen in patients with this disorder.
OBJECTIVES
We sought to determine whether pioglitazone treatment of gp91(phox-/-) mice enhanced phagocyte oxidant production and host defense.
METHODS
Wild-type and gp91(phox-/-) mice were treated with the PPARγ agonist pioglitazone, and phagocyte ROS and killing of S aureus were investigated.
RESULTS
As demonstrated by 3 different ROS-sensing probes, short-term treatment of gp91(phox-/-) mice with pioglitazone enhanced stimulated ROS production in neutrophils and monocytes from blood and neutrophils and inflammatory macrophages recruited to tissues. Mitochondria were identified as the source of ROS. Findings were replicated in human monocytes from patients with CGD after ex vivo pioglitazone treatment. Importantly, although mitochondrial (mt)ROS were deficient in gp91(phox-/-) phagocytes, their restoration with treatment significantly enabled killing of S aureus both ex vivo and in vivo.
CONCLUSIONS
Together, the data support the hypothesis that signaling from the NADPH oxidase under normal circumstances governs phagocyte mtROS production and that such signaling is lacking in the absence of a functioning phagocyte oxidase. PPARγ agonism appears to bypass the need for the NADPH oxidase for enhanced mtROS production and partially restores host defense in CGD.
Topics: Animals; Disease Models, Animal; Granulomatous Disease, Chronic; Humans; Male; Membrane Glycoproteins; Mice; Mice, Knockout; Mitochondria; Monocytes; NADPH Oxidase 2; NADPH Oxidases; Neutrophils; Oxidants; PPAR gamma; Phagocytes; Phagocytosis; Pioglitazone; Reactive Oxygen Species; Staphylococcus aureus; Superoxides; Thiazolidinediones
PubMed: 25498313
DOI: 10.1016/j.jaci.2014.10.034 -
Nature Immunology Mar 2011The NADPH oxidase of professional phagocytes has an important role in host defense against certain microbes, including tuberculous mycobacteria. The identification of...
The NADPH oxidase of professional phagocytes has an important role in host defense against certain microbes, including tuberculous mycobacteria. The identification of patients with rare inherited hypomorphic mutations in genes encoding components of this enzyme complex could produce new mechanistic insights.
Topics: Animals; Dendritic Cells; Humans; Macrophages; Membrane Glycoproteins; Models, Biological; NADPH Oxidase 2; NADPH Oxidases; Phagocytes
PubMed: 21321592
DOI: 10.1038/ni0311-201 -
Archives of Biochemistry and Biophysics Apr 2009Macrophages and neutrophils are essential elements of host cellular defense systems that function, at least in part, by generating respiration-driven oxidative toxins in... (Review)
Review
Macrophages and neutrophils are essential elements of host cellular defense systems that function, at least in part, by generating respiration-driven oxidative toxins in response to external stimuli. In both cells, encapsulation by phagocytosis provides a mechanism to direct the toxins against the microbes. The toxic chemicals formed by these two phagocytic cells differ markedly, as do the enzymatic catalysts that generate them. Nitrite ion is microbicidal under certain conditions, is generated by activated macrophages, and is present at elevated concentration levels at infection sites. In this review, we consider potential roles that nitrite might play in cellular disinfection by these phagocytes within the context of available experimental information. Although the suggested roles are plausible, based upon the chemical and biochemical reactivity of NO2(-), studies to date provide little support for their implementation within phagosomes.
Topics: Animals; Bacteria; Cyclooxygenase 1; Cyclooxygenase 2; Endothelium, Vascular; Humans; Leukocytes, Mononuclear; Macrophage Activation; Macrophages; Nitrites; Oxidative Stress; Phagocytes; Phagocytosis; Phagosomes
PubMed: 19402211
DOI: 10.1016/j.abb.2009.01.010 -
Frontiers in Immunology 2020The immediate and natural reaction to both infectious challenges and sterile insults (wounds, tissue trauma or crystal deposition) is an acute inflammatory response.... (Review)
Review
The immediate and natural reaction to both infectious challenges and sterile insults (wounds, tissue trauma or crystal deposition) is an acute inflammatory response. This inflammatory response is mediated by activation of the innate immune system largely comprising professional phagocytes (neutrophils and macrophages). Zebrafish () larvae possess many advantages as a model organism, including their genetic tractability and highly conserved innate immune system. Exploiting these attributes and the live imaging potential of optically transparent zebrafish larvae has greatly contributed to our understanding of how neutrophils and macrophages orchestrate the initiation and resolution phases of inflammatory responses. Numerous bacterial and fungal infection models have been successfully established using zebrafish as an animal model and studies investigating neutrophil and macrophage behavior to sterile insults have also provided unique insights. In this review we highlight how examining the larval zebrafish response to specific bacterial and fungal pathogens has uncovered cellular and molecular mechanisms behind a variety of phagocyte responses, from those that protect the host to those that are detrimental. We also describe how modeling sterile inflammation in larval zebrafish has provided an opportunity to dissect signaling pathways that control the recruitment, and fate, of phagocytes at inflammatory sites. Finally, we briefly discuss some current limitations, and opportunities to improve, the zebrafish model system for studying phagocyte biology.
Topics: Animals; Bacterial Infections; Inflammation; Mycoses; Phagocytes; Zebrafish
PubMed: 32582182
DOI: 10.3389/fimmu.2020.01094