P2 Receptors: Novel Disease Markers and Metabolic Checkpoints in Immune Cells

Vultaggio-Poma, Valentina; Virgilio, Francesco Di

doi:10.3390/biom12070983

Cited by 7 publications

(5 citation statements)

References 197 publications

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“…Thus, P2Y11R activation may also protect blood vessels from vascular injury induced from low pO 2 levels. In particular, the P2Y11 receptor, activated by ATP, has anti-inflammatory actions which could be implicated in endothelial cell protection in cardiovascular diseases [ 36 , 37 , 38 , 39 , 40 , 41 ].…”

Section: Resultsmentioning

confidence: 99%

Anoxia Rapidly Induces Changes in Expression of a Large and Diverse Set of Genes in Endothelial Cells

Antonelli

Scarpa

Bruzzone³

et al. 2023

IJMS

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Sinusoidal endothelial cells are the predominant vascular surface of the bone marrow and constitute the functional hematopoietic niche where hematopoietic stem and progenitor cells receive cues for self-renewal, survival, and differentiation. In the bone marrow hematopoietic niche, the oxygen tension is usually very low, and this condition affects stem and progenitor cell proliferation and differentiation and other important functions of this region. Here, we have investigated in vitro the response of endothelial cells to a marked decrease in O2 partial pressure to understand how the basal gene expression of some relevant biological factors (i.e., chemokines and interleukins) that are fundamental for the intercellular communication could change in anoxic conditions. Interestingly, mRNA levels of CXCL3, CXCL5, and IL-34 genes are upregulated after anoxia exposure but become downmodulated by sirtuin 6 (SIRT6) overexpression. Indeed, the expression levels of some other genes (such as Leukemia Inhibitory Factor (LIF)) that were not significantly affected by 8 h anoxia exposure become upregulated in the presence of SIRT6. Therefore, SIRT6 mediates also the endothelial cellular response through the modulation of selected genes in an extreme hypoxic condition.

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Section: Resultsmentioning

confidence: 99%

Anoxia Rapidly Induces Changes in Expression of a Large and Diverse Set of Genes in Endothelial Cells

Antonelli

Scarpa

Bruzzone³

et al. 2023

IJMS

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“…P2X7R expression is not restricted to brain tissue, and P2X7Rs can be found throughout the body, including the peripheral immune system (e.g., macrophages, T cells) [ 119 , 138 , 139 ]. Suggesting its potential as a diagnostic marker, a recent study by Giuliani et al showed that P2X7Rs can be shed into circulation, which seems to be increased under inflammatory conditions.…”

Section: The Role Of P2x7rs During Seizures and Epilepsymentioning

confidence: 99%

The P2X7 Receptor as a Mechanistic Biomarker for Epilepsy

Engel

2023

IJMS

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Epilepsy, characterized by recurrent spontaneous seizures, is a heterogeneous group of brain diseases affecting over 70 million people worldwide. Major challenges in the management of epilepsy include its diagnosis and treatment. To date, video electroencephalogram (EEG) monitoring is the gold-standard diagnostic method, with no molecular biomarker in routine clinical use. Moreover, treatment based on anti-seizure medications (ASMs) remains ineffective in 30% of patients, and, even if seizure-suppressive, lacks disease-modifying potential. Current epilepsy research is, therefore, mainly focussed on the identification of new drugs with a different mechanism of action effective in patients not responding to current ASMs. The vast heterogeneity of epilepsy syndromes, including differences in underlying pathology, comorbidities and disease progression, represents, however, a particular challenge in drug discovery. Optimal treatment most likely requires the identification of new drug targets combined with diagnostic methods to identify patients in need of a specific treatment. Purinergic signalling via extracellularly released ATP is increasingly recognized to contribute to brain hyperexcitability and, consequently, drugs targeting this signalling system have been proposed as a new therapeutic strategy for epilepsy. Among the purinergic ATP receptors, the P2X7 receptor (P2X7R) has attracted particular attention as a novel target for epilepsy treatment, with P2X7Rs contributing to unresponsiveness to ASMs and drugs targeting the P2X7R modulating acute seizure severity and suppressing seizures during epilepsy. In addition, P2X7R expression has been reported to be altered in the brain and circulation in experimental models of epilepsy and patients, making it both a potential therapeutic and diagnostic target. The present review provides an update on the newest findings regarding P2X7R-based treatments for epilepsy and discusses the potential of P2X7R as a mechanistic biomarker.

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“…While, activation of ComC leads to the release of C3 and C5 cleavage fragments—C3a and C5a anaphylatoxins that activate specific G-protein coupled receptors C3aR and C5aR, respectively, eATP released into extracellular space becomes a potent signaling mediator that activates ion-gated purinergic receptors from P2X family—P2X7 and P2X4 [ 19 ]. Receptors for C3a, C5a, and eATP are coupled to a superoxide-generating enzyme Nox2 complex that produces reactive oxygen species (ROS) [ 11 ], a potent activator of an intracellular PRR that is Nlrp3 inflammasome [ 12 ].…”

Section: A Novel Role For Reactive Oxygen Species (Ros) As Signaling ...mentioning

confidence: 99%

“…All these signaling pathways potentiates ROS-mediated activation of Nlrp3 inflammasome. In addition, Nlrp3 inflammasome may be additionally activated by cytosolic changes in concentration of K + and Ca 2+ as seen after stimulation of P2X7 and P2X4 receptors by eATP [ 19 , 20 ].…”

Section: A Novel Role For Reactive Oxygen Species (Ros) As Signaling ...mentioning

confidence: 99%

External Liver-Derived Complement and Intrinsic Present in Hematopoietic Stem/Progenitor Cells Complosome Modulate Cell Metabolism and Response to Stress

Thapa

Ratajczak

Kucia

et al. 2023

Stem Cell Rev and Rep

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Hematopoietic stem/progenitor cells (HSPCs) express receptors for complement cascade (ComC) cleavage fragments C3a and C5a and may respond to inflammation-related cues by sensing pathogen-associated molecular pattern molecules (PAMPs) released by pathogens as well as non-infectious danger associated molecular pattern molecules (DAMPs) or alarmin generated during stress/tissue damage sterile inflammation. To facilitate this HSPCs are equipped with C3a and C5a receptors, C3aR and C5aR, respectively, and express on the outer cell membrane and in cytosol pattern recognition receptors (PPRs) that sense PAMPs and DAMPs. Overall, danger-sensing mechanisms in HSPCs mimic those seen in immune cells, which should not surprise as hematopoiesis and the immune system develop from the same common stem cell precursor. This review will focus on the role of ComC-derived C3a and C5a that trigger nitric oxide synthetase-2 (Nox2) complex to release reactive oxygen species (ROS) that activate important cytosolic PRRs—Nlrp3 inflammasome, which orchestrates responsiveness of HSPCs to stress. Moreover, recent data indicate that in addition to circulating in peripheral blood (PB) activated liver-derived ComC proteins, a similar role plays ComC expressed and intrinsically activated in HSPCs known as “complosome”. We postulate that ComC triggered Nox2-ROS-Nlrp3 inflammasome responses, if they occur within non-toxic to cells' “hormetic range of activation”, positively regulate HSCs migration, metabolism, and proliferation. This sheds a new light on the immune-metabolic regulation of hematopoiesis. Graphical Abstract

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P2 Receptors: Novel Disease Markers and Metabolic Checkpoints in Immune Cells

Cited by 7 publications

References 197 publications

Anoxia Rapidly Induces Changes in Expression of a Large and Diverse Set of Genes in Endothelial Cells

Anoxia Rapidly Induces Changes in Expression of a Large and Diverse Set of Genes in Endothelial Cells

The P2X7 Receptor as a Mechanistic Biomarker for Epilepsy

External Liver-Derived Complement and Intrinsic Present in Hematopoietic Stem/Progenitor Cells Complosome Modulate Cell Metabolism and Response to Stress

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