Role of Purinergic Receptors in Cell Death and Cytokine Release in the Immune System

Ferrari, Davide; Martín, Vicente; Chiozzi, Paola; Susino, M. Dal; Falzoni, Simonetta; Ricciardi‐Castagnoli, Paola; Virgilio, Francesco Di

doi:10.1042/bst024560sc

Cited by 12 publications

(22 citation statements)

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“…In contrast, oxidized ATP did not inhibit NFAT activation in response to the Ca 2ϩ ionophore A23187, demonstrating that it did not interfere with the intracellular signaling of NFAT dephosphorylation and translocation. We also investigated the effect of NFAT activation in N9 derivative cells that lack the P2Z receptor but still express P2Y purinoreceptors (17,41). As shown in Fig.…”

Section: Nfat Is Activated Upon Stimulation With Extracellularmentioning

confidence: 99%

“…Maximal NFAT activation was obtained with 3 mM ATP, whereas a higher concentration of 5 mM was less effective. This dose dependence corresponds to other effects of P2Z purinoreceptor signal transduction in N9 cells (17) and mouse macrophages (18).…”

Section: Nfat Is Activated Upon Stimulation With Extracellularmentioning

confidence: 99%

“…ATP-Incubation of N9 mouse microglial cells with extracellular ATP elicits a rapid increase in the intracellular Ca 2ϩ concentration mediated by both the P2Z and P2Y receptors expressed in these cells (17). Whereas stimulation of P2Y receptors causes a transient Ca 2ϩ increase mainly from intracellular stores, activation of the P2Z receptor involves a longlasting Ca 2ϩ influx across the plasma membrane.…”

Section: Nfat Is Activated Upon Stimulation With Extracellularmentioning

confidence: 99%

“…It has been also postulated that P2Z receptor ligation is responsible for the formation of multinucleated giant cells during inflammatory granulomatous reactions (14). In addition, in lipopolysaccharide-primed macrophages and microglial cells, stimulation of the P2Z receptor induces the immediate release of interleukin (IL) 1 1␤, which is probably mediated by the activation of IL-1␤-converting enzyme (15)(16)(17)(18). Despite this accumulating evidence for an important function of the P2Z receptor in inflammatory processes, signaling events underlying these biological effects are almost entirely unknown.…”

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P2X7/P2Z Purinoreceptor-mediated Activation of Transcription Factor NFAT in Microglial Cells

Ferrari¹,

Stroh

Schulze‐Osthoff

1999

Journal of Biological Chemistry

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146

121

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ATP is released from neurons and other cell types during several physiological and stress conditions under which it exerts various biological effects upon binding to purinoreceptors. A rather peculiar purinoreceptor called P2X 7 /P2Z is expressed on microglial and other myeloic cells. Although increasing evidence implicates an important role for P2Z in inflammatory processes, little information exists about underlying signaling pathways. Here, we report that in N9 microglial cells, extracellular ATP potently activates nuclear factor of activated T cells (NFAT), a central transcription factor involved in cytokine gene expression. ATP activated NFAT rapidly (within 1 min), whereas activation of nuclear factor B was much delayed, with strikingly distinct kinetics. During ATP stimulation, both NFAT-1 and NFAT-2 were activated by a calcineurin-dependent pathway that required the influx of extracellular calcium ions. Based on the pharmacological profile, NFAT activation was specifically mediated by P2Z and not by other purinoreceptors. N9 cells that lacked P2Z but still expressed P2Y purinoreceptors failed to respond to NFAT activation. We conclude that P2Z-mediated NFAT activation may represent a novel mechanism by which extracellular ATP can modulate early inflammatory gene expression within the nervous and immune system.Large amounts of ATP and other nucleotides can be rapidly released from different cellular sources such as nerve terminals, antigen-stimulated T cells, activated platelets, endothelial cells, and other cell types under either physiological and pathological conditions such as hypoxia, stress, and tissue damage. Particularly in the immune and nervous system, extracellular ATP serves as a mediator of cell-to-cell communication by triggering a variety of biological responses including excitatory transmitter function, mitogenic stimulation, or induction of cell death (reviewed in Refs. 1-3). These effects are not the result of nonspecific membrane alterations but rather are mediated through the activation of specific surface molecules called P2 purinoreceptors (reviewed in Refs. 1, 4, and 5). At least two mechanistically distinct subclasses of P2 purinoreceptors are currently known. The metabotrophic P2Y receptors (formerly P2u, P2t, and P2y), which bind either UTP or ATP, initiate their biological effects through the G-proteincoupled activation of phospholipase C and subsequent Ca 2ϩ mobilization from intracellular stores. The P2X receptors are a distinct subfamily of receptors that are related to glutamate receptors and function as ligand-gated ion channels. Engagement of P2X receptors by ATP causes an increase in Ca 2ϩ permeability that is entirely dependent upon extracellular Ca 2ϩ ions. Recently, among the P2X subfamily, the molecular structure of the P2Z receptor, also called P2X 7 , has been elucidated (6, 7). The P2Z receptor contains two transmembrane domains and a large extracellular loop, structural features that are characteristic of members of the P2X family. Unlike other P2X receptors, the ...

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Section: Nfat Is Activated Upon Stimulation With Extracellularmentioning

confidence: 99%

Section: Nfat Is Activated Upon Stimulation With Extracellularmentioning

confidence: 99%

Section: Nfat Is Activated Upon Stimulation With Extracellularmentioning

confidence: 99%

mentioning

confidence: 99%

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P2X7/P2Z Purinoreceptor-mediated Activation of Transcription Factor NFAT in Microglial Cells

Ferrari¹,

Stroh

Schulze‐Osthoff

1999

Journal of Biological Chemistry

Self Cite

146

121

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“…Micromolar concentrations of ATP are required to activate the P2Y receptors, whereas millimolar (1-5 mM) concentrations of ATP are required to activate the P2X receptors. The ATP analog BzATP is a selective agonist at the P2X receptor and does not bind P2Y receptors (15,16). Oxidized ATP (oATP) is a specific antagonist of P2X 7 that binds irreversibly to the receptor and prevents its activation by ATP (17).…”

Section: Primary Rat Microglia Stimulated With Either Atp or 2-and 3-mentioning

confidence: 99%

P2X7 Mediates Superoxide Production in Primary Microglia and Is Up-regulated in a Transgenic Mouse Model of Alzheimer's Disease

Parvathenani

Tertyshnikova

Greco

et al. 2003

Journal of Biological Chemistry

439

370

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Primary rat microglia stimulated with either ATP or 2-and 3-O-(4-benzoylbenzoyl)-ATP (BzATPActivated microglia have been observed in patients suffering from both acute (stroke) and chronic (Alzheimer's disease) neurological disorders (1, 2). Microglia are believed to contribute to the progression of Alzheimer's disease (AD) 1 because these cells can release pro-inflammatory substances known to induce neurotoxicity (3). Reactive oxygen intermediates (ROIs), one of several pro-inflammatory substances released by microglia (4), are likely to play a very important role in AD because hallmark modifications of ROI damage such as lipid peroxidation and nitrotyrosine conjugates are characteristic of post-mortem AD brains (3). Hence, pro-inflammatory stimuli that promote microglial ROI production might contribute to the pathogenesis of AD.ATP is an important messenger in the brain and can be released from cells by both lytic and non-lytic mechanisms (5). ATP evokes a variety of biological responses in microglia (6 -9).The effects of ATP are mediated through interactions with the P2 purinoceptors, broadly classified into P2Y metabotropic and P2X ionotropic receptors (10). The P2Y receptors are G proteincoupled and P2X receptors are ligand-gated ion channels (10). Whereas the P2Y receptors are responsible for Ca 2ϩ release predominantly from intracellular stores, P2X receptors are responsible for Ca 2ϩ influx from extracellular sources. Microglia possess both P2Y and P2X receptors (11-13). The P2X 7 receptor is highly expressed by cells of the macrophage lineage, such as dendritic cells, alveolar macrophages, and microglia. Activation of the P2X 7 receptor is unique in triggering the formation of large nonselective membrane pores, permeable to molecules up to 900 Da which ultimately results in death of the cell (9, 14). ATP and ATP analogs have been used to characterize the role of P2 receptors in microglial activation. Micromolar concentrations of ATP are required to activate the P2Y receptors, whereas millimolar (1-5 mM) concentrations of ATP are required to activate the P2X receptors. The ATP analog BzATP is a selective agonist at the P2X receptor and does not bind P2Y receptors (15,16). Oxidized ATP (oATP) is a specific antagonist of P2X 7 that binds irreversibly to the receptor and prevents its activation by ATP (17). In this study, these pharmacological tools were used to determine the purinergic receptors involved in O 2. production in microglia.The P2X 7 receptor plays a role in the generation of superoxide in microglia. Our studies elucidate a putative signal transduction pathway that mediates this response. These studies also demonstrate that BzATP-and ATP-activated microglia can mediate neurotoxicity. Finally, a distinct alteration was detected in the staining pattern for P2X 7 receptor in a transgenic mouse model of AD, suggesting that P2X 7 receptor activation could play a contributing role in AD. MATERIALS AND METHODSReagents-Reagents not specified otherwise were obtained from Sigma. PD98059, SB203580, LY2940...

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Functional N‐Formyl Peptide Receptor 2 (FPR2) Antagonists Based on the Ureidopropanamide Scaffold Have Potential To Protect Against Inflammation‐Associated Oxidative Stress

et al. 2017

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Formyl peptide receptor-2 (FPR2) is a G protein-coupled receptor belonging to the N-formyl peptide receptor (FPR) family that plays critical roles in peripheral and brain inflammatory responses. FPR2 has been proposed as a target for the development of drugs that could facilitate the resolution of chronic inflammatory reactions by enhancing endogenous anti-inflammation systems. Starting from lead compounds previuosly identified in our laboratories, we designed a new series of ureidopropanamide derivatives with the goal of converting functional activity from agonism to antagonism and to develop new FPR2 antagonists. Although none of the compounds behaved as antagonist, some of the compounds were able to induce receptor desensitization, thus functionally behaving as antagonists. Evaluation of these compounds in an in vitro model of neuroinflammation showed that they reduced reactive oxygen species (ROS) production in mouse microglial N9 cells after stimulation with lipopolysaccharide (LPS). These FPR2 ligands may protect cells from damage due to inflammation-associated oxidative stress.

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Role of Purinergic Receptors in Cell Death and Cytokine Release in the Immune System

Cited by 12 publications

References 0 publications

P2X7/P2Z Purinoreceptor-mediated Activation of Transcription Factor NFAT in Microglial Cells

P2X7/P2Z Purinoreceptor-mediated Activation of Transcription Factor NFAT in Microglial Cells

P2X7 Mediates Superoxide Production in Primary Microglia and Is Up-regulated in a Transgenic Mouse Model of Alzheimer's Disease

Functional N‐Formyl Peptide Receptor 2 (FPR2) Antagonists Based on the Ureidopropanamide Scaffold Have Potential To Protect Against Inflammation‐Associated Oxidative Stress

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