ATP Stimulates Human Macrophages to Kill Intracellular Virulent <i>Mycobacterium tuberculosis</i> Via Calcium-Dependent Phagosome-Lysosome Fusion

Kusner, David J.; Barton, James A.

doi:10.4049/jimmunol.167.6.3308

Cited by 140 publications

(117 citation statements)

References 47 publications

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“…Confocal microscopy shows P2X7 in the phagosome membrane surrounding engulfed particles or bacteria [29,30] and recent reports suggest that P2X7 together with pannexin-1 may facilitate the delivery of bacterial products from phagosome lumen into the cytosol, where they can activate inflammasome assembly [31,32]. Moreover P2X7 has a role in facilitating the fusion of phagosome with lysosome by a process involving stimulation of phospholipase D activity presumably on the phagolysosomal membrane [33,34].…”

Section: Non-opsonized Beadsmentioning

confidence: 94%

A new role for the P2X7 receptor: a scavenger receptor for bacteria and apoptotic cells in the absence of serum and extracellular ATP

Wiley

2012

Purinergic Signalling

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The P2X7 receptor is widely recognized to mediate the proinflammatory effects of extracellular ATP. However this receptor in the absence of ATP may have a function unrelated to inflammation. Our data show that P2X7 expressed on the surface of monocyte/macrophages or on epithelial HEK-293 cells greatly augments the engulfment of latex beads and live and heat-killed bacteria by effector phagocyte in the absence of ATP and serum. The expression of P2X7 on the effector also confers the ability to phagocytose apoptotic target cells and an accumulation of P2X7 can be seen at the attachment point to the target. Activation of the P2X7 receptor by ATP causes a slow dissociation (over 10-15 min) of nonmuscle myosin from the P2X7 membrane complex and abolishes further P2X7-mediated phagocytosis of these targets. The recent crystal structure of the homologous zebrafish P2X4 receptor shows an exposed "nose" of the ectodomain (residues 115-162) which contains three of the five disulfide bonds conserved in all P2X receptors. Three short biotin-labeled peptides mimicking sequence of this exposed region bound to apoptotic target cells but not to either viable cells or to other target particles. All three peptides contained one or two cysteine residues and their replacement by alanine abolished peptide binding. These data implicate thiol-disulfide exchange reactions in the initial tethering of apoptotic cells to macrophage and establish P2X7 as one of the scavenger receptors involved in the recognition and removal of apoptotic cells in the absence of extracellular ATP and serum.

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Section: Non-opsonized Beadsmentioning

confidence: 94%

A new role for the P2X7 receptor: a scavenger receptor for bacteria and apoptotic cells in the absence of serum and extracellular ATP

Wiley

2012

Purinergic Signalling

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“…1A). Differentiation of THP-1 and U937 cells to a macrophage-like phenotype by incubation with IFN-␥, 1,25-dihydroxyvitamin D 3 , and retinoic acid (16,45,46), resulted in increased levels of both PLD1 and PLD2 in U937 cells, but no significant change was noted in THP-1 cells (Fig. 1A).…”

Section: Primary Human Macrophages and Myelomonocytic Cell Lines Exprmentioning

confidence: 97%

Phospholipases D1 and D2 Coordinately Regulate Macrophage Phagocytosis

Barton¹,

Bourgoin²,

Kusner

2004

The Journal of Immunology

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Phagocytosis is a fundamental feature of the innate immune system, required for antimicrobial defense, resolution of inflammation, and tissue remodeling. Furthermore, phagocytosis is coupled to a diverse range of cytotoxic effector mechanisms, including the respiratory burst, secretion of inflammatory mediators and Ag presentation. Phospholipase D (PLD) has been linked to the regulation of phagocytosis and subsequent effector responses, but the identity of the PLD isoform(s) involved and the molecular mechanisms of activation are unknown. We used primary human macrophages and human THP-1 promonocytes to characterize the role of PLD in phagocytosis. Macrophages, THP-1 cells, and other human myelomonocytic cells expressed both PLD1 and PLD2 proteins. Phagocytosis of complement-opsonized zymosan was associated with stimulation of the activity of both PLD1 and PLD2, as demonstrated by a novel immunoprecipitation-in vitro PLD assay. Transfection of dominant-negative PLD1 or PLD2 each inhibited the extent of phagocytosis (by 55–65%), and their combined effects were additive (reduction of 91%). PLD1 and PLD2 exhibited distinct localizations in resting macrophages and those undergoing phagocytosis, and only PLD1 localized to the phagosome membrane. The COS-7 monkey fibroblast cell line, which has been used as a heterologous system for the analysis of receptor-mediated phagocytosis, expressed PLD2 but not PLD1. These data support a model in which macrophage phagocytosis is coordinately regulated by both PLD1 and PLD2, with isoform-specific localization. Human myelomonocytic cell lines accurately model PLD-dependent signal transduction events required for phagocytosis, but the heterologous COS cell system does not.

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“…On a follow up of this work (Fairbairn et al, 2001), the same group showed that ATP treatment of infected macrophages led to an increase of fusion between phagosomes and lysosomes and further confirmed the ability to dissociate anti-mycobacterial activity from apoptosis. Similarly, Kusner & Barton (2001) Infection of macrophages and induction of apoptosis. After 9 days in culture, macrophages were incubated with a mycobacterial suspension of M. avium strain 25291.…”

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confidence: 99%

Induction of Mycobacterium avium growth restriction and inhibition of phagosome–endosome interactions during macrophage activation and apoptosis induction by picolinic acid plus IFNγ

Pais¹,

Appelberg²

2004

Microbiology

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Treatment of mouse macrophages with picolinic acid (PA) and c-interferon (IFNc) led to the restriction of Mycobacterium avium proliferation concomitant with the sequential acquisition of metabolic changes typical of apoptosis, mitochondrial depolarization, annexin V staining and caspase activation, over a period of up to 5 days. However, triggering of cell death by ATP, staurosporine or H 2 O 2 failed to affect mycobacterial viability. In contrast to untreated macrophages where extensive interactions between phagosomes and endosomes were observed, phagosomes from treated macrophages lost the ability to acquire endosomal dextran. N-Acetylcysteine was able to revert both the anti-mycobacterial activity of treated macrophages as well as the block in phagosome-endosome interactions. The treatment, however, induced only a minor increase in the acquisition of lysosomal markers, namely Lamp-1, and did not increase to any great extent the acidification of the phagosomes. These data thus suggest that the anti-mycobacterial activity of PA and IFNc depends on the interruption of intracellular vesicular trafficking, namely the blocking of acquisition of endosomal material by the microbe. INTRODUCTIONMycobacterium avium is an opportunistic pathogen that infects patients suffering from local or systemic deficiencies of the immune system (Falkinham, 1996). Resistance to infection is dependent on both innate mechanisms and acquired immunity through the development of antigenspecific CD4 + T cells (Appelberg, 1994;Holland, 1996). M. avium replicates inside the macrophage and is particularly resistant to the oxidative antimicrobial mechanisms of this phagocyte (Gomes & Appelberg, 2002;Gomes et al., 1999a). Like other pathogenic mycobacteria, M. avium has evolved survival strategies that interfere with the normal intracellular trafficking of vesicular compartments. After being internalized by macrophages, mycobacteria inhibit the fusion of the vacuole they inhabit with lysosomes, thus blocking maturation of the phagosomes into phagolysosomes and proliferating in vacuoles with early endosomal characteristics (Armstrong & d'Arcy-Hart, 1971;Clemens & Horwitz, 1995;Frehel et al., 1986;Russell et al., 1997). Several mechanisms associated with this inhibition have been described, such as reduced phagosomal acidification (Crowle et al., 1991;Sturgill-Koszycki et al., 1994;de Chastellier et al., 1995) due to exclusion of the vacuolar H + -ATPase , altered signalling pathways (Malik et al., 2001;Fratti et al., 2003), interference with the recycling of Rab proteins (Via et al., 1997), retention of the actin-binding coronin/TACO protein (Ferrari et al., 1999; see also Schuller et al., 2001, for a critical reappraisal of this issue), disorganization of the actin filament network (Guérin & de Chastellier, 2000) and tight apposition of the membrane vacuole to the surface of the pathogen, leading to altered exchange of fusion factors (de Chastellier & Thilo, 1997). However, mycobacterial phagosomes keep their ability to interact extensively wi...

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ATP Stimulates Human Macrophages to Kill Intracellular Virulent Mycobacterium tuberculosis Via Calcium-Dependent Phagosome-Lysosome Fusion

Cited by 140 publications

References 47 publications

A new role for the P2X7 receptor: a scavenger receptor for bacteria and apoptotic cells in the absence of serum and extracellular ATP

A new role for the P2X7 receptor: a scavenger receptor for bacteria and apoptotic cells in the absence of serum and extracellular ATP

Phospholipases D1 and D2 Coordinately Regulate Macrophage Phagocytosis

Induction of Mycobacterium avium growth restriction and inhibition of phagosome–endosome interactions during macrophage activation and apoptosis induction by picolinic acid plus IFNγ

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