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Extracellular ATP mediates inflammatory responses in colitis via P2 × 7 receptor signaling.

ABSTRACT: Extracellular purinergic products, particularly ATP, have recently been implicated to regulate immune cell functions and contribute to aberrant inflammatory responses of immune diseases. However, regulation of immune responses of colitis by extracellular ATP and its main receptor, P2 × 7, remains to be elucidated. In the study, we induced murine colitis by feeding mice with 4% dextran sulfate sodium (DSS), and noted dramatically heightened extracellular ATP levels in colon tissues during the progression of experimental colitis. Blockade of ATP release by carbenoxolone (CBX) treatment, or promoting ATP degradation by ATP diphosphohydrolase (apyrase), decreased extracellular ATP levels in colon tissues, attenuated DSS-induced colitis, whereas inhibition of extracellular ATP degradation by sodium metatungstate (POM-1) exacerbated tissue damage in the mice with colitis. Moreover, treatment with inhibitor of P2 × 7 receptor, A438079, decreased NFκB activation and active caspase-1 expression in lamina propria immune cells, downregulated proinflammatory cytokine production in colon tissues, and attenuated murine colitis. Collectively, these data suggest extracellular ATP participates in regulation of inflammatory responses of experimental colitis, through P2 × 7 receptor and inflammasome and NFκB signaling, which provides potential alternatives to the current clinical approaches to suppress extracellular ATP-mediated immune responsiveness.

SUBMITTER: Wan P

PROVIDER: S-EPMC4703960 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Extracellular ATP regulates various cellular functions by engaging multiple subtypes of P2 purinergic receptors. In many cell types, the ionotropic P2X7 receptor mediates pathological events such as inflammation and cell death. However, the importance of this receptor in chondrocytes remains largely unexplored. Here, we report the functional identification of P2X7 receptor in articular chondrocytes and investigate the involvement of P2X7 receptors in ATP-induced cytotoxicity. Chondrocytes were isolated from rabbit articular cartilage, and P2X7 receptor currents were examined using the whole-cell patch-clamp technique. ATP-induced cytotoxicity was evaluated by measuring caspase-3/7 activity, lactate dehydrogenase (LDH) leakage, and prostagrandin E2 (PGE2) release using microscopic and fluorimetric/colorimetric evaluation. Extracellular ATP readily evoked a cationic current without obvious desensitization. This ATP-activated current was dose related, but required millimolar concentrations. A more potent P2X7 receptor agonist, BzATP, also activated this current but at 100-fold lower concentrations. ATP-induced currents were largely abolished by selective P2X7 antagonists, suggesting a predominant role for the P2X7 receptor. RT-PCR confirmed the presence of P2X7 in chondrocytes. Heterologous expression of a rabbit P2X7 clone successfully reproduced the ATP-induced current. Exposure of chondrocytes to ATP increased caspase-3/7 activities, an effect that was totally abrogated by P2X7 receptor antagonists. Extracellular ATP also enhanced LDH release, which was partially attenuated by the P2X7 inhibitor. The P2X7 receptor-mediated elevation in apoptotic caspase signaling was accompanied by increased PGE2 release and was attenuated by inhibition of either phospholipase A2 or cyclooxygenase-2. This study provides direct evidence for the presence of functional P2X7 receptors in articular chondrocytes. Our results suggest that the P2X7 receptor is a potential therapeutic target in chondrocyte death associated with cartilage injury and disorders including osteoarthritis.

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Extracellular ATP mediates inflammatory responses in colitis via P2 × 7 receptor signaling.

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