Multiple P2X and P2Y receptor subtypes in mouse J774, spleen and peritoneal macrophages

Coutinho‐Silva, Robson; Ojcius, David M.; Górecki, Dariusz C.; Persechini, Pedro M.; Bisaggio, Rodrigo C.; Mendes, Anderson Nogueira; Marks, Joanne; Burnstock, Geoffrey; Dunn, Philip M.

doi:10.1016/j.bcp.2004.11.012

Cited by 63 publications

(60 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In our conditions, extracellular application of ATP, ADP, UTP, and UDP induced elevations of free intracellular Ca 2+ concentrations at doses consistent with the activation of P2Y1, 2, 4, and 6, in agreement with previously published results [59]. POM-1 inhibited the cytosolic Ca 2+ elevation induced by all these P2Y receptors (Fig.…”

Section: Discussionsupporting

confidence: 92%

See 1 more Smart Citation

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

Pimenta-dos-Reis

Torres

Quintana

et al. 2017

Purinergic Signalling

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 92%

“…2). eATP can also induce the influx of extracellular Ca 2+ through P2X1-7 channels, most of them previously described in peritoneal macrophages [59]. Here, we showed that POM-1 can partially inhibit the spike of Ca 2+ response triggered by P2X1-6, but not the sustained Ca 2+ increase evoked by the P2X7R activation (Fig.…”

Section: Discussionsupporting

confidence: 70%

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

Pimenta-dos-Reis

Torres

Quintana

et al. 2017

Purinergic Signalling

View full text Add to dashboard Cite

show abstract

“…the specific regulation of macrophage functions (25,(42)(43)(44). Several members of the P2Y and P2X receptors have been identified in cells of the immune system (40,44).…”

Section: Discussionmentioning

confidence: 99%

“…Several members of the P2Y and P2X receptors have been identified in cells of the immune system (40,44). Indeed, P2 agonists are increasingly viewed as a new class of innate immune system mediators following their release at sites of inflammation as a result of infection or cell damage.…”

Section: Discussionmentioning

confidence: 99%

“…In macrophages, much attention has been paid to P2X7 signaling because this receptor is highly expressed in these cells, and it has been involved in the regulation of stress signals (19,44). 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).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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.

show abstract

NTPDase1 governs P2X₇‐dependent functions in murine macrophages

et al. 2010

View full text Add to dashboard Cite

P2X 7 receptor is an adenosine triphosphate (ATP)-gated ion channel within the multiprotein inflammasome complex. Until now, little is known about regulation of P2X 7 effector functions in macrophages. In this study, we show that nucleoside triphosphate diphosphohydrolase 1 (NTPDase1)/CD39 is the dominant ectonucleotidase expressed by murine peritoneal macrophages and that it regulates P2X 7 -dependent responses in these cells. Macrophages isolated from NTPDase1-null mice (Entpd1) were devoid of all ADPase and most ATPase activities when compared with WT macrophages (Entpd1 1/1 ). Entpd1À/À macrophages exposed to millimolar concentrations of ATP were more susceptible to cell death, released more IL-1b and IL-18 after TLR2 or TLR4 priming, and incorporated the fluorescent dye Yo-Pro-1 more efficiently (suggestive of increased pore formation) than Entpd1 1/1 cells. Consistent with these observations, NTPDase1 regulated P2X 7 -associated IL-1b release after synthesis, and this process occurred independently of, and prior to, cytokine maturation by caspase-1. NTPDase1 also inhibited IL-1b release in vivo in the air pouch inflammatory model. Exudates of LPS-injected Entpd1 À/À mice had significantly higher IL-1b levels when compared with Entpd1 1/1 mice. Altogether, our studies suggest that NTPDase1/CD39 plays a key role in the control of P2X 7 -dependent macrophage responses.Key words: ATP-induced death . CD39 . IL-1b . Macrophage . Nucleoside triphosphate diphosphohydrolase 1Supporting Information available online IntroductionMonocytes/macrophages are myeloid inflammatory cells that play important roles in innate host defense and immune regulation [1]. For example, these cells represent the major source of IL-1 during inflammation, a cytokine playing a pivotal role in chronic inflammatory diseases such as rheumatoid arthritis and several neurodegenerative disorders [2,3]. Monocytes/macrophages express functional P2 receptors specific for extracellular nucleotides, which serve as ''danger'' signals and initiate the immune response [4]. At the mRNA level, primary monocytes express the ion-channel P2X 1,4,5,7 receptors and the G-protein-coupled P2Y 1,2,4,6,11-13 receptors, and macrophages express the same receptor subtypes except P2Y 13 [5]. P2Y 1 , P2Y 2 , [6][7][8]. P2X 7 receptor (formerly P2Z) plays a key role in inflammation [9,10]. P2X 7 receptor activation by extracellular adenosine triphosphate (ATP), released under inflammatory conditions, is a co-stimulus for a massive release of mature and bioactive cytokines of the IL-1 family, such as IL-1b and IL-18, from LPS-primed macrophages and other cell types [11]. The activation of P2X 7 in leucocytes also induces cell death, intracellular pathogen clearance and membrane trafficking [12][13][14]. While nano to low micromolar nucleotide concentrations are sufficient for the activation of other P2 receptors, P2X 7 is activated by far higher concentrations of ATP (in the order of the millimolar (mM)) and/ or by mono adenosine diphosphate (ADP) ribosylation [15].The ...

show abstract

Multiple P2X and P2Y receptor subtypes in mouse J774, spleen and peritoneal macrophages

Cited by 63 publications

References 47 publications

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

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

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

NTPDase1 governs P2X₇‐dependent functions in murine macrophages

Contact Info

Product

Resources

About

Multiple P2X and P2Y receptor subtypes in mouse J774, spleen and peritoneal macrophages

Cited by 63 publications

References 47 publications

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

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

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

NTPDase1 governs P2X7‐dependent functions in murine macrophages

Contact Info

Product

Resources

About

NTPDase1 governs P2X₇‐dependent functions in murine macrophages