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The P2X7 Receptor in Inflammatory Diseases: Angel or Demon?

ABSTRACT: Under physiological conditions, adenosine triphosphate (ATP) is present at low levels in the extracellular milieu, being massively released by stressed or dying cells. Once outside the cells, ATP and related nucleotides/nucleoside generated by ectonucleotidases mediate a high evolutionary conserved signaling system: the purinergic signaling, which is involved in a variety of pathological conditions, including inflammatory diseases. Extracellular ATP has been considered an endogenous adjuvant that can initiate inflammation by acting as a danger signal through the activation of purinergic type 2 receptors-P2 receptors (P2Y G-protein coupled receptors and P2X ligand-gated ion channels). Among the P2 receptors, the P2X7 receptor is the most extensively studied from an immunological perspective, being involved in both innate and adaptive immune responses. P2X7 receptor activation induces large-scale ATP release via its intrinsic ability to form a membrane pore or in association with pannexin hemichannels, boosting purinergic signaling. ATP acting via P2X7 receptor is the second signal to the inflammasome activation, inducing both maturation and release of pro-inflammatory cytokines, such as IL-1? and IL-18, and the production of reactive nitrogen and oxygen species. Furthermore, the P2X7 receptor is involved in caspases activation, as well as in apoptosis induction. During adaptive immune response, P2X7 receptor modulates the balance between the generation of T helper type 17 (Th17) and T regulatory (Treg) lymphocytes. Therefore, this receptor is involved in several inflammatory pathological conditions. In infectious diseases and cancer, P2X7 receptor can have different and contrasting effects, being an angel or a demon depending on its level of activation, cell studied, type of pathogen, and severity of infection. In neuroinflammatory and neurodegenerative diseases, P2X7 upregulation and function appears to contribute to disease progression. In this review, we deeply discuss P2X7 receptor dual function and its pharmacological modulation in the context of different pathologies, and we also highlight the P2X7 receptor as a potential target to treat inflammatory related diseases.

SUBMITTER: Savio LEB

PROVIDER: S-EPMC5808178 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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The P2X7 Receptor in Inflammatory Diseases: Angel or Demon?

Savio Luiz E B LEB de Andrade Mello Paola P da Silva Cleide Gonçalves CG Coutinho-Silva Robson R

Frontiers in pharmacology 20180206

Under physiological conditions, adenosine triphosphate (ATP) is present at low levels in the extracellular milieu, being massively released by stressed or dying cells. Once outside the cells, ATP and related nucleotides/nucleoside generated by ectonucleotidases mediate a high evolutionary conserved signaling system: the purinergic signaling, which is involved in a variety of pathological conditions, including inflammatory diseases. Extracellular ATP has been considered an endogenous adjuvant tha ...[more]

PMID: 29467654

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Project description:A decline in breast cancer incidence has been attributed to the reduction in hormone replacement therapy (HRT) prescriptions since the publication of the landmark WHIT paper in 2003. Concurrently, a relationship between HRT and cerebrovascular disease incidence has also been suggested. No generalized analysis of HRT prescription rates and breast cancer incidence rates that included more than seven years of data. We hypothesized that detailed analysis of SEER data would clarify the relationship between HRT use and breast cancer incidence. Given the large decline in HRT prescription rates uncovered, analyses of potential complications were also conducted, with the understanding that a small effect or one limited to a subpopulation, such as a single race, might not be detected.Incidence rates (per 100,000 women) and standard errors for ductal and lobular breast carcinomas, and endometrioid /endometrial carcinomas in women over 50 years were obtained from the Surveillance, Epidemiology, and End Results (SEER) database 1992-2012. From the Medical Expenditure Panel Survey 1996-2012 weighted counts and standard errors of hormone replacement therapy (HRT) prescriptions for women over 50 years were obtained. Using the National Hospital Discharge Survey (NHDS), 1996-2010 weighted counts and standard errors of femoral neck fractures, total hip replacements, acute myocardial infarctions, and cerebral infarctions were obtained for 50+ year men and women. Weighted counts and standard errors were divided by US census figures and multiplied by 100,000. Joinpoint regression was used to analyze rates.Beginning 2001, HRT prescription rates dropped dramatically, 2001-2012 AAPC -14.9 (95% CI -17.4, -12.4). Breast cancer rates, which began to decline in 1999, increased after 2003; 2012 rates were similar to those seen in 2001 for both ductal, AAPC 0.1 (-0.4, 0.6) and lobular, AAPC 0.5 (-0.4, 1.5), carcinoma. Endometrial carcinoma rates increased, 2001-2012 AAPC 3.5 (3.1, 3.8), arguing against a negative effect of HRT discontinuation of endometrial carcinoma. Tests for parallelism failed to detect APC differences among genders for femoral neck fractures (P = 0.24), for total hip replacements (P = 0.11), for myocardial infarctions (P = 0.10), or for cerebral infarctions (P = 0.19), precluding any assignment of general effect on these disorders by HRT.Using SEER data, we demonstrated that changes in breast cancer rates cannot be explained by HRT prescription rate changes.

Project description:BACKGROUND & AIMS:The severity of sepsis can be linked to excessive inflammatory responses resulting in hepatic injury. P2X7 receptor activation by extracellular ATP (eATP) exacerbates inflammation by augmenting cytokine production; while CD39 (ENTPD1) scavenges eATP to generate adenosine, thereby limiting P2X7 activation and resulting in A2A receptor stimulation. We aim to determine how the functional interaction of P2X7 receptor and CD39 control the macrophage response, and consequently impact on sepsis and liver injury. METHODS:Sepsis was induced by cecal ligation and puncture in C57BL/6 wild-type (WT) and CD39-/- mice. Several in vitro assays were performed using peritoneal or bone marrow derived macrophages to determine CD39 ectonucleotidase activity and its role in sepsis-induced liver injury. RESULTS:CD39 expression in macrophages limits ATP-P2X7 receptor pro-inflammatory signaling. P2X7 receptor paradoxically boosts CD39 activity. Inhibition and/or deletion of P2X7 receptor in LPS-primed macrophages attenuates cytokine production and inflammatory signaling as well as preventing ATP-induced increases in CD39 activity. Septic CD39-/- mice exhibit higher levels of inflammatory cytokines and show more pronounced liver injury than WT mice. Pharmacological P2X7 blockade largely prevents tissue damage, cell apoptosis, cytokine production, and the activation of inflammatory signaling pathways in the liver from septic WT, while only attenuating these outcomes in CD39-/- mice. Furthermore, the combination of P2X7 blockade with adenosine A2A receptor stimulation completely inhibits cytokine production, the activation of inflammatory signaling pathways, and protects septic CD39-/- mice against liver injury. CONCLUSIONS:CD39 attenuates sepsis-associated liver injury by scavenging eATP and ultimately generating adenosine. We propose boosting of CD39 would suppress P2X7 responses and trigger adenosinergic signaling to limit systemic inflammation and restore liver homeostasis during the acute phase of sepsis. Lay summary: CD39 expression in macrophages limits P2X7-mediated pro-inflammatory responses, scavenging extracellular ATP and ultimately generating adenosine. CD39 genetic deletion exacerbates sepsis-induced experimental liver injury. Combinations of a P2X7 antagonist and adenosine A2A receptor agonist are hepatoprotective during the acute phase of abdominal sepsis.

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The P2X7 Receptor in Inflammatory Diseases: Angel or Demon?

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The P2X7 Receptor in Inflammatory Diseases: Angel or Demon?

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