The role of p2x7 receptor in infectious inflammatory diseases and the influence of ectonucleotidases

Morandini, Ana Carolina; Savio, Luiz Eduardo Baggio; Coutinho‐Silva, Robson

doi:10.4103/2319-4170.127803

Cited by 76 publications

(45 citation statements)

References 105 publications

(119 reference statements)

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“…8,9 Adenosine triphosphate (ATP) may be secreted into the extracellular space as a result of cellular damage or TLR activation, as part of different pathogen-associated molecular patterns (PAMPs) that induce leukocyte activation and migration to the site of infection. 10,11 Through the activation of P2 receptors, extracellular ATP (eATP) can initiate inflammation by acting as a ‘danger’ signal in the extracellular medium.…”

Section: Introductionmentioning

confidence: 99%

“…10,11 Through the activation of P2 receptors, extracellular ATP (eATP) can initiate inflammation by acting as a ‘danger’ signal in the extracellular medium. 9,12 The P2 receptor family comprises of P2Y G-protein coupled receptors and P2X (P2X1-7) ligand-gated ion channels. 13,14 The P2X7 receptor has been the most extensively studied, 9 as activation of this receptor induces maturation and release of pro-inflammatory cytokines, such as IL-1β, 15 together with activation of acid sphingomyelinase 16 and the production of reactive nitrogen and oxygen species.…”

Section: Introductionmentioning

confidence: 99%

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CD39 limits P2X7 receptor inflammatory signaling and attenuates sepsis-induced liver injury

Savio

Mello

Figliuolo

et al. 2017

Journal of Hepatology

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146

105

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Background & Aims The severity of sepsis can be linked to excessive inflammatory responses resulting in hepatic injury. P2X7 receptor activation by extracellular ATP (eATP) exacerbates inflammation by augmenting cytokine production; while CD39 (ENTPD1) scavenges eATP to generate adenosine, thereby limiting P2X7 activation and resulting in A2A receptor stimulation. We aim to determine the functional interaction of P2X7 and A2A receptors on controlling macrophage response, consequently impacting the outcome of sepsis and liver injury. Methods Sepsis was induced by cecal ligation and puncture in C57BL/6 wild-type (WT) and CD39−/− mice. Several in vitro assays were performed using peritoneal or bone marrow derived macrophages to determine CD39 ectonucleotidase activity and its role in sepsis-induced liver injury. Results CD39 expression in macrophages limits ATP-P2X7 receptor pro-inflammatory signaling. P2X7 receptor paradoxically boosts CD39 activity. Inhibition and/or deletion of P2X7 receptor in LPS-primed macrophages attenuates cytokine production and inflammatory signaling as well as preventing ATP-induced increases in CD39 activity. Septic CD39−/− mice exhibit higher levels of inflammatory cytokines and show more pronounced liver injury than WT mice. Pharmacological P2X7 blockade largely prevents tissue damage, cell apoptosis, cytokine production, and the activation of inflammatory signaling pathways in the liver from septic WT, while only attenuating these outcomes in CD39−/− mice. Furthermore, the combination of P2X7 blockade with adenosine A2A receptor stimulation completely inhibits cytokine production, the activation of inflammatory signaling pathways, and protects septic CD39−/− mice against liver injury. Conclusions CD39 attenuates sepsis-associated liver injury by scavenging eATP and ultimately generating adenosine. We propose boosting of CD39 would suppress P2X7 responses and trigger adenosinergic signaling to limit systemic inflammation and restore liver homeostasis during the acute phase of sepsis.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CD39 limits P2X7 receptor inflammatory signaling and attenuates sepsis-induced liver injury

Savio

Mello

Figliuolo

et al. 2017

Journal of Hepatology

Self Cite

146

105

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“…The P2X7 receptor (P2X7R) is an extracellular ATP-gated cation channel expressed in epithelial cells and immune effector cells and is involved in the regulation of pro-inflammatory cytokine production 11 , apoptosis and autophagy induction 12 , and host defenses against infectious pathogens 13 . In the absence of this receptor, septic mice exhibited improved survival, decreased levels of NO and pro-inflammatory cytokines, reduced peritoneal cell apoptosis, and produced less pronounced morphological changes 14, 15 .…”

Section: Introductionmentioning

confidence: 99%

Systemic blockade of P2X7 receptor protects against sepsis-induced intestinal barrier disruption

Ren

Chen

et al. 2017

Sci Rep

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Sepsis, during which the intestinal epithelial barrier is frequently disrupted, remains a challenging and life-threatening problem in clinical practice. The P2X7 receptor (P2X7R) is a non-selective adenosine triphosphate-gated cation channel present in macrophages that is involved in inflammatory responses. However, little is known about the role of P2X7R in macrophages during sepsis-induced intestinal barrier disruption. In this study, mice were treated with the P2X7R antagonist A740003 or the agonist BzATP by intra-peritoneal injection after the induction of gut-origin sepsis. The survival rates, inflammatory responses, intestinal barrier integrity, macrophage marker expression, and ERK and NF-κB activities were evaluated. Intestinal macrophages were also isolated and studied after exposure to Brilliant Blue G or BzATP. We found that a systemic P2X7R blockade downregulated sepsis-induced inflammatory responses and attenuated intestinal barrier dysfunction based on the evidence that mice in the A740003-treated group exhibited alleviated pro-inflammatory cytokine synthesis, intestinal hyperpermeability, epithelial apoptosis rates and tight junction damage compared with the septic mice. These changes were partly mediated by the inhibition of M1 macrophages activation via ERK/NF-κB pathways. Our data presented herein show that a P2X7R blockade could be a potential therapeutic target for the treatment of sepsis-induced intestinal barrier dysfunction.

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“…Extracellular nucleotides, such as the ATP released by dying cells and by activated immune cells during inflammation, are important danger signals involved in immune response [6], participating in both paracrine [7] and autocrine [8] signaling pathways. In inflammatory processes, high extracellular ATP levels generated by tissue damage or secretion are recognized by the immune system as a danger signal, activating purinergic P2 receptors that contribute to a proinflammatory response [9]. …”

Section: Introductionmentioning

confidence: 99%

Macrophage P2X7 Receptor Function Is Reduced during Schistosomiasis: Putative Role of TGF-β1

Oliveira

Nanini

Savio

et al. 2014

Mediators of Inflammation

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Schistosomiasis is a chronic inflammatory disease whose macrophages are involved in immunopathology modulation. Although P2X7 receptor signaling plays an important role in inflammatory responses mediated by macrophages, no reports have examined the role of P2X7 receptors in macrophage function during schistosomiasis. Thus, we evaluated P2X7 receptor function in peritoneal macrophages during schistosomiasis using an ATP-induced permeabilization assay and measurements of the intracellular Ca2+ concentration. ATP treatment induced significantly less permeabilization in macrophages from S. mansoni-infected mice than in control cells from uninfected animals. Furthermore, P2X7-mediated increases in intracellular Ca2+ levels were also reduced in macrophages from infected mice. TGF-β1 levels were increased in the peritoneal cavity of infected animals, and pretreatment of control macrophages with TGF-β1 reduced ATP-induced permeabilization, mimicking the effect of S. mansoni infection. Western blot and qRT-PCR data showed no difference in P2X7 protein and mRNA between uninfected, infected, and TGF-β1-treated groups. However, immunofluorescence analysis revealed reduced cell surface localization of P2X7 receptors in macrophages from infected and TGF-β1-treated mice compared to controls. Therefore, our data suggest that schistosomiasis reduces peritoneal macrophage P2X7 receptor signaling. This effect is likely due to the fact that infected mice have increased levels of TGF-β1, which reduces P2X7 receptor cell surface expression.

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The role of p2x7 receptor in infectious inflammatory diseases and the influence of ectonucleotidases

Cited by 76 publications

References 105 publications

CD39 limits P2X7 receptor inflammatory signaling and attenuates sepsis-induced liver injury

CD39 limits P2X7 receptor inflammatory signaling and attenuates sepsis-induced liver injury

Systemic blockade of P2X7 receptor protects against sepsis-induced intestinal barrier disruption

Macrophage P2X7 Receptor Function Is Reduced during Schistosomiasis: Putative Role of TGF-β1

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