Purinergic Signaling in Liver Pathophysiology.
Ontology highlight
ABSTRACT:
SUBMITTER: Jain S
PROVIDER: S-EPMC8385492 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Adenosine triphosphate (ATP) is essential for the myriad of metabolic processes upon which life is based and is known widely as the universal energy currency unit of intracellular biologic reactions. ATP, adenosine diphosphate, adenosine, as well as other purines and pyrimidines also serve as ubiquitous extracellular mediators which function through the activation of specific receptors (viz. P2 receptors for nucleotides and purinergic P1 receptors for adenosine). Extracellular nucleotides are rapidly converted to nucleosides, such as adenosine, by highly regulated plasma membrane ectonucleotidases that modulate many of the normal biological and metabolic processes in the liver - such as gluconeogenesis and insulin signaling. Under inflammatory conditions, as with ischemia reperfusion, sepsis or metabolic stress, ATP and other nucleotides can also act as 'damage-associated molecular patterns' causing inflammasome activation in innate immune cells and endothelium resulting in tissue damage. The phosphohydrolysis of ATP by ectonucleotidases, such as those of the CD39/ENTPD family, results in the generation of immune suppressive adenosine, which in turn markedly limits inflammatory processes. Experimental studies by others and our group have implicated purinergic signaling in experimental models of hepatic ischemia reperfusion and inflammation, transplant rejection, hepatic regeneration, steatohepatitis, fibrosis and cancer, amongst others. Expression of ectonucleotidases on sinusoidal endothelial, stellate or immune cells allows for homeostatic integration and linking of the control of vascular inflammatory and immune cell reactions in the liver. CD39 expression also identifies hepatic myeloid dendritic cells and efficiently distinguishes T-regulatory-type cells from other resting or activated T cells. Our evolving data strongly indicate that CD39 serves as a key 'molecular switch' and is an integral component of the suppressive machinery of myeloid, dendritic and T cells. Increased understanding of mechanisms of extracellular ATP scavenging and specifically conversion to nucleosides by ectonucleotidases of the CD39 family have also led to novel insights into the exquisite balance of nucleotide P2-receptor and adenosinergic P1-receptor signaling in inflammatory and hepatic diseases. Further, CD39 and other ectonucleotidases exhibit genetic polymorphisms in humans which alter levels of expression/function and are associated with predisposition to inflammatory and immune diseases, diabetes and vascular calcification, amongst other problems. Development of therapeutic strategies targeting purinergic signaling and ectonucleotidases offers promise for the management of disordered inflammation and aberrant immune reactivity.
| S-EPMC6310169 | biostudies-literature
Project description:Huntington's disease (HD) is a devastating, progressive, and fatal neurodegenerative disorder inherited in an autosomal dominant manner. This condition is characterized by motor dysfunction (chorea in the early stage, followed by bradykinesia, dystonia, and motor incoordination in the late stage), psychiatric disturbance, and cognitive decline. The neuropathological hallmark of HD is the pronounced neuronal loss in the striatum (caudate nucleus and putamen). The striatum is related to the movement control, flexibility, motivation, and learning and the purinergic signaling has an important role in the control of these events. Purinergic signaling involves the actions of purine nucleotides and nucleosides through the activation of P2 and P1 receptors, respectively. Extracellular nucleotide and nucleoside-metabolizing enzymes control the levels of these messengers, modulating the purinergic signaling. The striatum has a high expression of adenosine A2A receptors, which are involved in the neurodegeneration observed in HD. The P2X7 and P2Y2 receptors may also play a role in the pathophysiology of HD. Interestingly, nucleotide and nucleoside levels may be altered in HD animal models and humans with HD. This review presents several studies describing the relationship between purinergic signaling and HD, as well as the use of purinoceptors as pharmacological targets and biomarkers for this neurodegenerative disorder.
| S-EPMC8281137 | biostudies-literature
Project description:Purinergic signaling regulates a diverse and biologically relevant group of processes in the liver. However, progress of research into functions regulated by purinergic signals in the liver has been hampered by the complexity of systems probed. Specifically, there are multiple liver cell subpopulations relevant to hepatic functions, and many of these have been effectively modeled in human cell lines. Furthermore, there are more than 20 genes relevant to purinergic signaling, each of which has distinct functions. Hence, we felt the need to categorize genes relevant to purinergic signaling in the best characterized human cell line models of liver cell subpopulations. Therefore, we investigated the expression of adenosine receptor, P2X receptor, P2Y receptor, and ecto-nucleotidase genes via RT-PCR in the following cell lines: LX-2, hTERT, FH11, HepG2, Huh7, H69, and MzChA-1. We believe that our findings will provide an excellent resource to investigators seeking to define functions of purinergic signals in liver physiology and liver disease pathogenesis.
| S-EPMC4272373 | biostudies-literature
Project description:Extracellular ATP represents an important autocrine/paracrine signaling molecule within the liver. The mechanisms responsible for ATP release are unknown, and alternative pathways have been proposed, including either conductive ATP movement through channels or exocytosis of ATP-enriched vesicles, although direct evidence from liver cells has been lacking. Utilizing dynamic imaging modalities (confocal and total internal reflection fluorescence microscopy and luminescence detection utilizing a high sensitivity CCD camera) at different scales, including confluent cell populations, single cells, and the intracellular submembrane space, we have demonstrated in a model liver cell line that (i) ATP release is not uniform but reflects point source release by a defined subset of cells; (ii) ATP within cells is localized to discrete zones of high intensity that are approximately 1 mum in diameter, suggesting a vesicular localization; (iii) these vesicles originate from a bafilomycin A(1)-sensitive pool, are depleted by hypotonic exposure, and are not rapidly replenished from recycling of endocytic vesicles; and (iv) exocytosis of vesicles in response to cell volume changes depends upon a complex series of signaling events that requires intact microtubules as well as phosphoinositide 3-kinase and protein kinase C. Collectively, these findings are most consistent with an essential role for exocytosis in regulated release of ATP and initiation of purinergic signaling in liver cells.
| S-EPMC2832965 | biostudies-literature
Project description:Extracellular purines (ATP and adenosine) are ubiquitous intercellular messengers. During tissular damage, they function as damage-associated molecular patterns (DAMPs). In this context, purines announce tissue alterations to initiate a reparative response that involve the formation of the inflammasome complex and the recruitment of specialized cells of the immune system. The present review focuses on the role of the purinergic system in liver damage, mainly during the onset and development of fibrosis. After hepatocellular injury, extracellular ATP promotes a signaling cascade that ameliorates tissue alterations to restore the hepatic function. However, if cellular damage becomes chronic, ATP orchestrates an aberrant reparative process that results in severe liver diseases such as fibrosis and cirrhosis. ATP and adenosine, their receptors, and extracellular ectonucleotidases are mediators of unique processes that will be reviewed in detail.
| S-EPMC6923300 | biostudies-literature
Project description:Extracellular ATP activates P2 purinergic receptors. Whether purinergic signaling is functionally coupled to cellular senescence is largely unknown. We find that oxidative stress induced release of ATP and caused senescence in human lung fibroblasts. Inhibition of P2 receptors limited oxidative stress-induced senescence, while stimulation with exogenous ATP promoted premature senescence. Pharmacological inhibition of P2Y11 receptor (P2Y11R) inhibited premature senescence induced by either oxidative stress or ATP, while stimulation with a P2Y11R agonist was sufficient to induce cellular senescence. Our data show that both extracellular ATP and a P2Y11R agonist induced calcium (Ca++) release from the endoplasmic reticulum (ER) and that either inhibition of phospholipase C or intracellular Ca++ chelation impaired ATP-induced senescence. We also find that Ca++ that was released from the ER, following ATP-mediated activation of phospholipase C, entered mitochondria in a manner dependent on P2Y11R activation. Once in mitochondria, excessive Ca++ promoted the production of reactive oxygen species in a P2Y11R-dependent fashion, which drove development of premature senescence of lung fibroblasts. Finally, we show that conditioned medium derived from senescent lung fibroblasts, which were induced to senesce through the activation of ATP/P2Y11R-mediated signaling, promoted the proliferation of triple-negative breast cancer cells and their tumorigenic potential by secreting amphiregulin. Our study identifies the existence of a novel purinergic signaling pathway that links extracellular ATP to the development of a protumorigenic premature senescent phenotype in lung fibroblasts that is dependent on P2Y11R activation and ER-to-mitochondria calcium signaling.
| S-EPMC11002311 | biostudies-literature
Project description:Endometriosis is an estrogen-dependent gynecological disease, with an associated chronic inflammatory component, characterized by the presence of endometrial tissue outside the uterine cavity. Its predominant symptom is pain, a condition notably altering the quality of life of women with the disease. This review is intended to exhaustively gather current knowledge on purinergic signaling in endometriosis-associated pain. Altered extracellular ATP hydrolysis, due to changes in ectonucleotidase activity, has been reported in endometriosis; the resulting accumulation of ATP in the endometriotic microenvironment points to sustained activation of nucleotide receptors (P2 receptors) capable of generating a persistent pain message. P2X3 receptor, expressed in sensory neurons, mediates nociceptive, neuropathic, and inflammatory pain, and is enrolled in endometriosis-related pain. Pharmacological inhibition of P2X3 receptor is under evaluation as a pain relief treatment for women with endometriosis. The role of other ATP receptors is also discussed here, e.g., P2X4 and P2X7 receptors, which are involved in inflammatory cell-nerve and microglia-nerve crosstalk, and therefore in inflammatory and neuropathic pain. Adenosine receptors (P1 receptors), by contrast, mainly play antinociceptive and anti-inflammatory roles. Purinome-targeted drugs, including nucleotide receptors and metabolizing enzymes, are potential non-hormonal therapeutic tools for the pharmacological management of endometriosis-related pain.
| S-EPMC7697899 | biostudies-literature
Project description:Cancer is a complex expression of an altered state of cellular differentiation associated with severe clinical repercussions. The effort to characterize this pathological entity to understand its underlying mechanisms and visualize potential therapeutic strategies has been constant. In this context, some cellular (enhanced duplication, immunological evasion), metabolic (aerobic glycolysis, failure in DNA repair mechanisms) and physiological (circadian disruption) parameters have been considered as cancer hallmarks. The list of these hallmarks has been growing in recent years, since it has been demonstrated that various physiological systems misfunction in well-characterized ways upon the onset and establishment of the carcinogenic process. This is the case with the purinergic system, a signaling pathway formed by nucleotides/nucleosides (mainly adenosine triphosphate (ATP), adenosine (ADO) and uridine triphosphate (UTP)) with their corresponding membrane receptors and defined transduction mechanisms. The dynamic equilibrium between ATP and ADO, which is accomplished by the presence and regulation of a set of ectonucleotidases, defines the pro-carcinogenic or anti-cancerous final outline in tumors and cancer cell lines. So far, the purinergic system has been recognized as a potential therapeutic target in cancerous and tumoral ailments.
| S-EPMC7407645 | biostudies-literature
Project description:Inflammation triggered by metabolic imbalance, also called metainflammation, is low-grade inflammation caused by the components involved in metabolic syndrome (MetS), including central obesity and impaired glucose tolerance. This phenomenon is mainly due to excess nutrients and energy, and it contributes to the pathogenesis of osteoarthritis (OA). OA is characterized by the progressive degeneration of articular cartilage, which suffers erosion and progressively becomes thinner. Purinergic signaling is involved in several physiological and pathological processes, such as cell proliferation in development and tissue regeneration, neurotransmission and inflammation. Adenosine and ATP receptors, and other members of the signaling pathway, such as AMP-activated protein kinase (AMPK), are involved in obesity, type 2 diabetes (T2D) and OA progression. In this review, we focus on purinergic regulation in osteoarthritic cartilage and how different components of MetS, such as obesity and T2D, modulate the purinergic system in OA. In that regard, we describe the critical role in this disease of receptors, such as adenosine A2A receptor (A2AR) and ATP P2X7 receptor. Finally, we also assess how nucleotides regulate the inflammasome in OA.
| S-EPMC7485330 | biostudies-literature
Project description:The skeleton constantly interacts and adapts to the physical world. We have previously reported that physiologically relevant mechanical forces lead to small repairable membrane injuries in bone-forming osteoblasts, resulting in release of ATP and stimulation of purinergic (P2) calcium responses in neighboring cells. The goal of this study was to develop a theoretical model describing injury-related ATP and ADP release, their extracellular diffusion and degradation, and purinergic responses in neighboring cells. After validation using experimental data for intracellular free calcium elevations, ATP, and vesicular release after mechanical stimulation of a single osteoblast, the model was scaled to a tissue-level injury to investigate how purinergic signaling communicates information about injuries with varying geometries. We found that total ATP released, peak extracellular ATP concentration, and the ADP-mediated signaling component contributed complementary information regarding the mechanical stimulation event. The total amount of ATP released governed spatial factors, such as the maximal distance from the injury at which purinergic responses were stimulated. The peak ATP concentration reflected the severity of an individual cell injury, allowing to discriminate between minor and severe injuries that released similar amounts of ATP because of differences in injury repair, and determined temporal aspects of the response, such as signal propagation velocity. ADP-mediated signaling became relevant only in larger tissue-level injuries, conveying information about the distance to the injury site and its geometry. Thus, we identified specific features of extracellular ATP and ADP spatiotemporal signals that depend on tissue mechanoresilience and encode the severity, scope, and proximity of the mechanical stimulus.
| S-EPMC6531813 | biostudies-literature