Extracellular ATP protects against sepsis through macrophage P2X7 purinergic receptors by enhancing intracellular bacterial killing

Csóka, Balázs; Németh, Zoltán; Törő, Gábor; Idzko, Marco; Zech, Andreas; Koscsó, Balázs; Spolarics, Zoltán; Antonioli, Luca; Cseri, Karolina; Erdélyi, Katalin; Pacher, Pál; Haskó, György

doi:10.1096/fj.15-272450

Cited by 120 publications

(106 citation statements)

References 49 publications

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“…Moreover, inhibition of P2X7 by a selective antagonist suppressed the NLRP3/ASC/caspase-1 signaling cascade and IL-1␤ release, arresting further lung injury (57). It has been shown that P2X7 also plays a role in the regulation of the immune system, such as in protecting against sepsis (7). Signaling through P2X7 on macrophages was found to reduce sepsis proliferation and provide antibacterial effects (7).…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that P2X7 also plays a role in the regulation of the immune system, such as in protecting against sepsis (7). Signaling through P2X7 on macrophages was found to reduce sepsis proliferation and provide antibacterial effects (7). A study using P2X7 KO mice demonstrated that the receptor is required for development of the inflammatory response associated with sepsis (50).…”

Section: Discussionmentioning

confidence: 99%

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Deletion of P2X7 attenuates hyperoxia-induced acute lung injury via inflammasome suppression

Galam

Rajan

Failla

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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-Increasing evidence shows that hyperoxia is a serious complication of oxygen therapy in acutely ill patients that causes excessive production of free radicals leading to hyperoxia-induced acute lung injury (HALI). Our previous studies have shown that P2X7 receptor activation is required for inflammasome activation during HALI. However, the role of P2X7 in HALI is unclear. The main aim of this study was to determine the effect of P2X7 receptor gene deletion on HALI. Wild-type (WT) and P2X7 knockout (P2X7 KO) mice were exposed to 100% O 2 for 72 h. P2X7 KO mice treated with hyperoxia had enhanced survival in 100% O 2 compared with the WT mice. Hyperoxia-induced recruitment of inflammatory cells and elevation of IL-1␤, TNF-␣, monocyte chemoattractant protein-1, and IL-6 levels were attenuated in P2X7 KO mice. P2X7 deletion decreased lung edema and alveolar protein content, which are associated with enhanced alveolar fluid clearance. In addition, activation of the inflammasome was suppressed in P2X7-deficient alveolar macrophages and was associated with suppression of IL-1␤ release. Furthermore, P2X7-deficient alveolar macrophage in type II alveolar epithelial cells (AECs) coculture model abolished protein permeability across mouse type II AEC monolayers. Deletion of P2X7 does not lead to a decrease in epithelial sodium channel expression in cocultures of alveolar macrophages and type II AECs. Taken together, these findings show that deletion of P2X7 is a protective factor and therapeutic target for the amelioration of hyperoxia-induced lung injury. acute lung injury; P2X7; NLRP3; inflammasome; hyperoxia ACUTE LUNG INJURY (ALI) IS a major clinical problem in the United States, accounting for one of the primary causes of in-hospital hypoxemic respiratory failure leading to morbidity and mortality (48). Prolonged exposure to hyperoxia has been conclusively demonstrated to cause ALI (22,58,62). Furthermore, numerous cardiovascular and pulmonary diseases require oxygen therapy (22, 28 -30, 58). Therefore, it is pertinent to understand the mechanism of damage in ALI, wherein the pathology manifests as alveolar damage from immune cell infiltration and pulmonary edema (31,63).Prolonged exposure to oxygen concentrations of FI O 2 Ͼ 0.8 has previously been shown to cause mortality in small animal and higher-order primate models (26). Hyperoxia-induced lung injury contributes to increasing the production of reactive oxygen species (ROS), inflammatory cytokines, as well as exudative pulmonary edema, collagen deposition, and damage to the alveolar epithelium (26, 32). Thus, using hyperoxia as a form of oxygen toxicity is clinically relevant to study the pathophysiology of ALI. In ALI, the disruption of the fine balance between proinflammatory and anti-inflammatory agents is the basic pathology with a concomitant activation of apoptotic signals (33, 59, 62). IL-1␤ was discovered to be one of the early inflammatory cytokines to appear in ALI patients and cause the release of additional cytokines (18). The caspase-1-mediated acti...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Deletion of P2X7 attenuates hyperoxia-induced acute lung injury via inflammasome suppression

Galam

Rajan

Failla

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Xiang et al showed that ATP offered protection from peritonitis in mice infected with Staphylococcus aureus and Escherichia coli [12]. Csoka et al demonstrated the ability of macrophages to increase intracellular killing of E. coli through purinergic receptors during sepsis, highlighting the beneficial effects of ATP through the inflammasome in an in vivo model [19]. …”

Section: Introductionmentioning

confidence: 99%

Inflammasome Activation by ATP Enhances Citrobacter rodentium Clearance through ROS Generation

Bording-Jorgensen¹,

Alipour²,

Danesh³

et al. 2017

Cell Physiol Biochem

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Background: Nod-like receptor family, pyrin domain containing 3 (NLRP3) is an important cytosolic sensor of cellular stress and infection. Once activated, NLRP3 forms a multiprotein complex (inflammasome) that triggers the maturation and secretion of interleukin (IL)-1β and IL-18. We aimed to define the consequences of NLRP3 induction, utilizing exogenous adenosine triphosphate (ATP) as an inflammasome activator, to determine if inflammasome activation increases macrophage killing of Citrobacter rodentium and define mechanisms. Methods: Bacterial survival was measured using a gentamicin protection assay. Inflammasome activation or inhibition in mouse J774A.1 macrophages were assessed by measuring IL-1β; cytokines and reactive oxygen species (ROS) were measured by ELISA and DCFDA, respectively. Results: Activation of the inflammasome increased bacterial killing by macrophages and its inhibition attenuated this effect with no impact on phagocytosis or cell death. Furthermore, inflammasome activation suppressed pro-inflammatory cytokines during infection, possibly due to more effective bacterial killing. While the infection increased ROS production, this effect was reduced by inflammasome inhibitors, indicating that ROS is inflammasome-dependent. ROS inhibitors increased bacterial survival in the presence of ATP, suggesting that inflammasome-induced bacterial killing is mediated, at least in part, by ROS activity. Conclusion: Improving inflammasome activity during infection may increase bacterial clearance by macrophages and reduce subsequent microbe-induced inflammation.

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“…TNF-α, IL-1β, and NO release in LPS-primed macrophages is blocked by POM-1 eATP, acting via P2X7R, induces production and release of IL-1β by activation of the NLRP3/caspase-1 complex [13]. We examined the effects of POM-1 on IL-1β and TNF-α secretion by LPS-primed macrophages in response to 3 mM ATP.…”

Section: Bleb Formation In Response To Atp Is Not Blocked By Pom-1mentioning

confidence: 99%

“…P2X7R activation has been widely studied as a trigger of the NLRP3 inflammasome, but eATP through P2X7R can modulate immune functions even in an inflammasomeindependent manner [13]. P2X7R can induce cell death, cytokine release, killing of intracellular pathogens, and membrane blebbing [14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

POM-1 inhibits P2 receptors and exhibits anti-inflammatory effects in macrophages

Pimenta-dos-Reis

Torres

Quintana

et al. 2017

Purinergic Signalling

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Extracellular nucleotides can modulate the immunological response by activating purinergic receptors (P2Rs) on the cell surface of macrophages, dendritic, and other immune cells. In particular, the activation of P2X7R can induce release of cytokines and cell death as well as the uptake of large molecules through the cell membrane by a mechanism still poorly understood. Polyoxotungstate-1 (POM-1) has been proposed as a potent inhibitor of ecto-nucleotidases, enzymes that hydrolyze extracellular nucleotides, regulating the activity of P2Rs. However, the potential impact of POM-1 on P2Rs has not been evaluated. Here, we used fluorescent dye uptake, cytoplasmic free Ca 2+ concentration measurement, patch-clamp recordings, scanning electron microscopy, and quantification of inflammatory mediators to investigate the effects of POM-1 on P2Rs of murine macrophages. We observed that POM-1 blocks the P2YR-dependent cytoplasmic Ca 2+ increase and has partial effects on the cytoplasmic Ca 2+ , increasing dependence on P2XRs. POM-1 can inhibit the events related with ATP-dependent inflammasome activation, anionic dye uptake, and also the opening of large conductance channels, which are associated with P2X7R-dependent pannexin-1 activation. On the other hand, this compound has no effects on cationic fluorescent dye uptake, apoptosis, and bleb formation, also dependent on P2X7R. Moreover, POM-1 can be considered an anti-inflammatory compound, because it prevents TNF-α and nitric oxide release from LPStreated macrophages.

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Extracellular ATP protects against sepsis through macrophage P2X7 purinergic receptors by enhancing intracellular bacterial killing

Cited by 120 publications

References 49 publications

Deletion of P2X7 attenuates hyperoxia-induced acute lung injury via inflammasome suppression

Deletion of P2X7 attenuates hyperoxia-induced acute lung injury via inflammasome suppression

Inflammasome Activation by ATP Enhances Citrobacter rodentium Clearance through ROS Generation

POM-1 inhibits P2 receptors and exhibits anti-inflammatory effects in macrophages

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