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

Ping Wan,Jiang Chen,Xiaopeng Liu,Yan Xiong,Aiping Bai,Nonghua Lu,Yuan Guo,Yuping Ren

doi:10.1038/srep19108

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.

Highlights

Extracellular purinergic products, has significant impact on experimental colitis[16]
Because P2 × 7 receptor is dominantly expressed by lamina propria cells and myenteric plexus[18,25,26], and upregulation of P2 × 7 receptor in intestinal mucosa exhibits potential in the pathogenesis of Crohn’s disease[25], we explored the mechanisms of ATP-P2 × 7 receptor signaling in regulation of inflammatory responses of experimental colitis
We discussed the pivotal role of extracellular purinergic signaling, ATP-P2 × 7 receptor signaling, in regulation of inflammatory responses of experimental colitis

Summary

Introduction

Extracellular purinergic products, has significant impact on experimental colitis[16]. We determined extracellular ATP levels in colon tissues during the progression of DSS-induced colitis. In consistence with decreased extracellular ATP levels, management with CBX attenuated DSS-induced colon inflammation, evidenced with regained body weight (Fig. 2b), and decreased disease activity index (DAI) scores (Fig. 2c).

Results

Conclusion