Transient P2X7 Receptor Activation Triggers Macrophage Death Independent of Toll-like Receptors 2 and 4, Caspase-1, and Pannexin-1 Proteins

Hanley, Peter J.; Kronlage, Moritz; Kirschning, Carsten J.; Rey, Adriana del; Virgilio, Francesco Di; Leipziger, Jens; Chessell, Iain P.; Sargin, Sarah; Филиппов, М. А.; Lindemann, Otto; Mohr, Simon; Königs, Volker; Schillers, Hermann; Bähler, Martin; Schwab, Albrecht

doi:10.1074/jbc.m111.332676

Cited by 63 publications

(67 citation statements)

References 41 publications

(79 reference statements)

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“…It is well known that P2X7 activation by ATP participates in the regulation of the innate response in macrophages, including the killing of intracellular pathogens, the release and maturation of proinflammatory cytokines (i.e., IL-1b and IL-18) (51-55), and the increase in PGE 2 levels (19). The mechanisms involved in these actions implicate a rise in Ca 2+ influx and in the activation of the MAPK signaling pathways (56)(57)(58). However, less is known regarding the role of P2Y receptors in macrophage function.…”

Section: Discussionmentioning

confidence: 99%

Selective Impairment of P2Y Signaling by Prostaglandin E2 in Macrophages: Implications for Ca2+-Dependent Responses

Través

Pimentel-Santillana

Carrasquero

et al. 2013

The Journal of Immunology

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Extracellular nucleotides have been recognized as important modulators of inflammation via their action on specific pyrimidine receptors (P2). This regulation coexists with the temporal framework of proinflammatory and proresolution mediators released by the cells involved in the inflammatory response, including macrophages. Under proinflammatory conditions, the expression of cyclooxygenase-2 leads to the release of large amounts of PGs, such as PGE2, that exert their effects through EP receptors and other intracellular targets. The effect of these PGs on P2 receptors expressed in murine and human macrophages was investigated. In thioglycollate-elicited and alternatively activated macrophages, PGE2 selectively impairs P2Y but not P2X7 Ca2+ mobilization. This effect is absent in LPS-activated cells and is specific for PGE2 because it cannot be reproduced by other PGs with cyclopentenone structure. The inhibition of P2Y responses by PGE2 involves the activation of nPKCs (PKCε) and PKD that can be abrogated by selective inhibitors or by expression of dominant-negative forms of PKD. The inhibition of P2Y signaling by PGE2 has an impact on the cell migration elicited by P2Y agonists in thioglycollate-elicited and alternatively activated macrophages, which provide new clues to understand the resolution phase of inflammation, when accumulation of PGE2, anti-inflammatory and proresolving mediators occurs.

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Section: Discussionmentioning

confidence: 99%

Selective Impairment of P2Y Signaling by Prostaglandin E2 in Macrophages: Implications for Ca2+-Dependent Responses

Través

Pimentel-Santillana

Carrasquero

et al. 2013

The Journal of Immunology

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“…One difficulty in the effort to better understand this question is the fact that often researchers use the ATP-dependent cationic dye uptake as a measure of pannexin-1 involvement in a particular phenomenon [9,67,71]. However, we [10] and others [11] showed that the P2X7-dependent dye uptake has at least two associated pathways, with differences between cations and anions.…”

Section: Discussionmentioning

confidence: 89%

“…Hanley and collaborators showed that activation of P2X7R induces blebbing, uptake of cationic dyes, caspase-3/7 activation, and cell death independent of caspase-1 and pannexin-1 [67]. P2X7R-dependent blebbing involves both Ca 2+ -dependent and Ca 2+ -independent mechanisms [52,[68][69][70] and is dissociated from IL-1β secretion or capase-1 activation [52].…”

Section: Discussionmentioning

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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“…Some of the early events may be transient, as part of the yet undefined ''find me'' signals, or alternatively they may take different pathways resulting in cell death. In conjunction with activation of the P2X7 receptors, as it has been already shown in melanoma cells (Hanley et al 2012), for example, one could postulate that by mediating apoptotic actions of extracellular nucleotides this may have a potential role in clinical practice as a novel therapeutic target. It also appears that the hepatocytes are more sensitive and susceptible to these early intracellular events leading to apoptosis.…”

Section: Discussionmentioning

confidence: 95%

“…Recent publications indicated that P2X7 receptor activation and Ca 2? overload may act as a death trigger for native mouse macrophages independent of Pannexin 1 and proinflammatory caspase-1 and TLR signaling (Hanley et al 2012;Jalilian et al 2012;Nishida et al 2012). YP1 positivity may be an early indicator of P2X7 receptor activation.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of YO-PRO-1 as an early marker of apoptosis following radiofrequency ablation of colon cancer liver metastases

et al. 2013

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Radiofrequency (RF) ablation (RFA) is a minimally invasive treatment for colorectal-cancer liver metastases (CLM) in selected nonsurgical patients. Unlike surgical resection, RFA is not followed by routine pathological examination of the target tumor and the surrounding liver tissue. The aim of this study was the evaluation of apoptotic events after RFA. Specifically, we evaluated YO-PRO-1 (YP1), a green fluorescent DNA marker for cells with compromised plasma membrane, as a potential, early marker of cell death. YP1 was applied on liver tissue adherent on the RF electrode used for CLM ablation, as well as on biopsy samples from the center and the margin of the ablation zone as depicted by dynamic CT immediately after RFA. Normal pig and mouse liver tissues were used for comparison. The same samples were also immunostained for fragmented DNA (TUN-EL assay) and for active mitochondria (anti-OxPhos antibody). YP1 was also used simultaneously with propidium iodine (PI) to stain mouse liver and samples from ablated CLM. Following RFA of human CLM, more than 90 % of cells were positive for YP1. In nonablated, dissected pig and mouse liver however, we found similar YP1 signals (93.1 % and 65 %, respectively). In samples of intact mouse liver parenchyma, there was a significantly smaller proportion of YP1 positive cells (22.7 %). YP1 and PI staining was similar for ablated CLM. However in dissected normal mouse liver there was initial YP1 positivity and complete absence of the PI signal and only later there was PI signal. Conclusion: This is the first time that YP1 was applied in liver parenchymal tissue (rather than cell culture). The results suggest that YP1 is a very sensitive marker of early cellular events reflecting an early and widespread plasma membrane injury that allows YP1 penetration into the cells.

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Transient P2X7 Receptor Activation Triggers Macrophage Death Independent of Toll-like Receptors 2 and 4, Caspase-1, and Pannexin-1 Proteins

Cited by 63 publications

References 41 publications

Selective Impairment of P2Y Signaling by Prostaglandin E2 in Macrophages: Implications for Ca2+-Dependent Responses

Selective Impairment of P2Y Signaling by Prostaglandin E2 in Macrophages: Implications for Ca2+-Dependent Responses

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

Evaluation of YO-PRO-1 as an early marker of apoptosis following radiofrequency ablation of colon cancer liver metastases

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