Overview of the role of purinergic signaling and insights into its role in cancer therapy.

Innovation of cancer therapy has received a dramatic acceleration over the last fifteen years thanks to the introduction of the novel immune checkpoint inhibitors (ICI). On the other hand, the conspicuous scientific knowledge accumulated in purinergic signaling since the early seventies is finally being transferred to the clinic. Several Phase I/II clinical trials are currently underway to investigate the effect of drugs interfering with purinergic signaling as stand-alone or combination therapy in cancer.

The P2X7 Receptor is a Master Regulator of Microparticle and Mitochondria Exchange in Mouse Microglia.

Microparticles (MPs) are secreted by all cells, where they play a key role in intercellular communication, differentiation, inflammation, and cell energy transfer. P2X7 receptor (P2X7R) activation by extracellular ATP (eATP) causes a large MP release and affects their contents in a cell-specific fashion. We investigated MP release and functional impact in microglial cells from P2X7R-WT or P2X7R-KO mice, as well as mouse microglial cell lines characterized for high (N13-P2X7RHigh) or low (N13-P2X7RLow) P2X7R expression.

The Coming of Age of the P2X7 Receptor in Diagnostic Medicine.

The discovery of the P2X7 receptor (P2X7R, originally named P2Z) in immune cells, its cloning, and the identification of its role in a multiplicity of immune-mediated diseases raised great hopes for the development of novel and more potent anti-inflammatory medicaments. Unfortunately, such hopes were partially deluded by the unsatisfactory results of most early clinical trials. This failure substantially reduced the interest of the pharmaceutical and biotech industries in the clinical development of P2X7R-targeted therapies.

The shed P2X7 receptor is an index of adverse clinical outcome in COVID-19 patients.

Introduction: The pathophysiology of the Corona Virus Disease 2019 (COVID-19) is incompletely known. A robust inflammatory response caused by viral replication is a main cause of the acute lung and multiorgan injury observed in critical patients. Inflammasomes are likely players in COVID-19 pathogenesis.

Fetal bovine serum contains biologically available ATP.

ATP is a ubiquitous extracellular messenger released in a wide number of pathophysiological conditions. ATP is known to be present in minute amounts in the extracellular space in healthy tissues and in the blood, and to modulate a multiplicity of cell responses. Cell culture systems are widely used to explore purinergic signaling.

Extracellular ATP: A powerful inflammatory mediator in the central nervous system.

Nucleotides play a crucial role in extracellular signaling across species boundaries. All the three kingdoms of life (Bacteria, Archea and Eukariota) are responsive to extracellular ATP (eATP) and many release this and other nucleotides. Thus, eATP fulfills different functions, many related to danger-sensing or avoidance reactions.

Modulation of Cell Energy Metabolism by the P2X7 Receptor.

For many years the P2X7 receptor (P2X7R) was considered the prototypic cytolytic receptor due to its ability to cause dramatic changes in plasma membrane permeability, eventually leading to cell death. However, later studies revealed that controlled P2X7R activation has beneficial effects on cell metabolism and nowadays our perception of the physiological role of this receptor has radically changed. Some of the biochemical pathways underlying the trophic effect of the P2X7R are being unveiled, thus disclosing an unanticipated role of P2X7Rs in mitochondrial and glycolytic metabolism.

Signalling by extracellular nucleotides in health and disease.

Nucleotides are released from all cells through regulated pathways or as a result of plasma membrane damage or cell death. Outside the cell, nucleotides act as signalling molecules triggering multiple responses via specific plasma membrane receptors of the P2 family. In the nervous system, purinergic signalling has a key function in neurotransmission.

Extracellular ATP is increased by release of ATP-loaded microparticles triggered by nutrient deprivation.

: Caloric restriction improves the efficacy of anti-cancer therapy. This effect is largely dependent on the increase of the extracellular ATP concentration in the tumor microenvironment (TME). Pathways for ATP release triggered by nutrient deprivation are largely unknown.

Ectonucleotidases in Acute and Chronic Inflammation.

Ectonucleotidases are extracellular enzymes with a pivotal role in inflammation that hydrolyse extracellular purine and pyrimidine nucleotides, e.g., ATP, UTP, ADP, UDP, AMP and NAD.

Mitochondrial P2X7 Receptor Localization Modulates Energy Metabolism Enhancing Physical Performance.

Basal expression of the P2X7 receptor (P2X7R) improves mitochondrial metabolism, Adenosine 5'-triphosphate (ATP) synthesis, and overall fitness of immune and non-immune cells. We investigated P2X7R contribution to energy metabolism and subcellular localization in fibroblasts (mouse embryo fibroblasts and HEK293 human fibroblasts), mouse microglia (primary brain microglia, and the N13 microglia cell line), and heart tissue. The P2X7R localizes to mitochondria, and its lack (1) decreases basal respiratory rate, ATP-coupled respiration, maximal uncoupled respiration, resting mitochondrial potential, mitochondrial matrix Ca level, (2) modifies expression pattern of oxidative phosphorylation enzymes, and (3) severely affects cardiac performance.

The P2X7 Receptor Is Overexpressed in the Lesional Skin of Subjects Affected by Hidradenitis Suppurativa: A Preliminary Study.

Background: P2X receptors (P2XRs) are plasma membrane channels involved in the modulation of immune responses. The role of the P2X7 receptor (P2X7R) has never been investigated in hidradenitis suppurativa (HS), which is a recurrent skin disease characterized by inflammatory nodules, scarring, and suppuration.

Objective: Our aim was to investigate by immunohistochemistry (IHC) P2X7R, NLRP3 (NOD-like receptor family, pyrin domain-containing 3), and interleukin-1β (IL-1β) expression in HS lesions compared to healthy control (HC) skin.

Extreme thrombocytosis in systemic juvenile idiopathic arthritis. A case report.

Background: Systemic onset juvenile idiopathic arthritis (SoJIA) is a rare inflammatory disorder characterized by remitting fevers, evanescent rash, generalized lymphadenopathy, hepatomegaly/splenomegaly, and/or serositis.

Case Presentation: Here we report the case of a 5 years-old girl with SoJIA complicated by severe thrombocytosis. Treatment with the Interleukin-1β (IL-1β) receptor antagonist Anakinra caused a fast reduction of blood platelets and of the associated systemic inflammatory response.

P2X7 Receptor Expression in Patients With Serositis Related to Systemic Lupus Erythematosus.

P2X7R is an extracellular ATP-gated receptor involved in inflammatory and autoimmune processes mainly acting through NLPR3-inflammasome activation and IL-1β release, also implicated in lymphocyte proliferation and cellular apoptosis. Several observations from animal models and patients' studies highlight a possible link between P2X7R-NLRP3 axis and Systemic Lupus Erythematosus (SLE) pathogenesis. The P2X7R-inflammasome axis in addition to the direct production of IL-1β and IL-18, indirectly mediates the release of other cytokines implicated in the pathogenesis of SLE, such as IL-6.

The P2X7 Receptor Is Shed Into Circulation: Correlation With C-Reactive Protein Levels.

The P2X7 receptor (P2X7R) is a key pro-inflammatory plasma membrane receptor responsible for NLRP3 inflammasome activation and IL-1β release. Various inflammatory plasma membrane receptors (e.g.

Amyloid β-dependent mitochondrial toxicity in mouse microglia requires P2X7 receptor expression and is prevented by nimodipine.

Previous data from our laboratory show that expression of the P2X7 receptor (P2X7R) is needed for amyloid β (Aβ)-stimulated microglia activation and IL-1β release in vitro and in vivo. We also showed that Aβ-dependent stimulation is inhibited by the dihydropyridine nimodipine at an intracellular site distal to the P2X7R. In the present study, we used the N13 microglia cell line and mouse primary microglia from wt and P2rx7-deleted mice to test the effect of nimodipine on amyloid β (Aβ)-dependent NLRP3 inflammasome expression and function, and on mitochondrial energy metabolism.

Extracellular nucleotides and nucleosides as signalling molecules.

Extracellular nucleotides, mainly ATP, but also ADP, UTP, UDP and UDP-sugars, adenosine, and adenine base participate in the "purinergic signalling" pathway, an ubiquitous system of cell-to-cell communication. Fundamental pathophysiological processes such as tissue homeostasis, wound healing, neurodegeneration, immunity, inflammation and cancer are modulated by purinergic signalling. Nucleotides can be released from cells via unspecific or specific mechanisms.

Non-nucleotide Agonists Triggering P2X7 Receptor Activation and Pore Formation.

The P2X7 receptor (P2X7R) is a ligand-gated plasma membrane ion channel belonging to the P2X receptor subfamily activated by extracellular nucleotides. General consensus holds that the physiological (and maybe the only) agonist is ATP. However, scattered evidence generated over the last several years suggests that ATP might not be the only agonist, especially at inflammatory sites.

The P2X7 receptor: A main player in inflammation.

Damage associated molecular patterns (DAMPs) are intracellular molecules released from infected or injured cells to activate inflammatory and reparatory responses. One of the most ancient and conserved DAMPs is extracellular ATP that exerts its phlogistic activity mainly through activation of the P2X7 receptor (P2X7R). The P2X7R is an ATP gated ion channel, expressed by most immune cells, including the monocyte-derived cell lineages, T and B lymphocytes and their precursors.

The P2X7 Receptor in Infection and Inflammation.

Adenosine triphosphate (ATP) accumulates at sites of tissue injury and inflammation. Effects of extracellular ATP are mediated by plasma membrane receptors named P2 receptors (P2Rs). The P2R most involved in inflammation and immunity is the P2X7 receptor (P2X7R), expressed by virtually all cells of innate and adaptive immunity.

The P2X7 Receptor-Interleukin-1 Liaison.

Interleukin-1β (IL-1β) plays a central role in stimulation of innate immune system and inflammation and in several chronic inflammatory diseases. These include rare hereditary conditions, e.g.

P2X7 Receptor Orchestrates Multiple Signalling Pathways Triggering Inflammation, Autophagy and Metabolic/Trophic Responses.

P2X7 receptor is an ion channel activated by extracellular adenosine trisphosphate (eATP) that attracted increasing attention for its role in immune reactions, neurobiology and oncology. As receptor for an extracellular ligand, P2X7 activates a series of intracellular signalling pathways mainly via alterations of the ion permeability, but also through formation of a large unselective pore and direct interaction with other proteins. Here we wish to give an overview on the main biochemical paths initiated by P2X7 activation by revising recent and established literature on P2X7-triggered signalling cascades leading to cell death, inflammatory and immune response activation, proliferation and metabolism modulation.

Purinergic signalling in autoimmunity: A role for the P2X7R in systemic lupus erythematosus?

Purinergic signalling plays a crucial role in immunity and autoimmunity. Among purinergic receptors, the P2X7 receptor (P2X7R) has an undisputed role as it is expressed to high level by immune cells, triggers cytokine release and modulates immune cell differentiation. In this review, we focus on evidence supporting a possible role of the P2X7R in the pathogenesis of systemic lupus erythematosus (SLE).