Wan Ping, Liu Xiaopeng, Xiong Yan, Ren Yuping, Chen Jiang, Lu Nonghua, Guo Yuan, Bai Aiping
Department of Gastroenterology, the First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China.
Department of surgery, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong Province, China.
Sci Rep. 2016 Jan 7;6:19108. doi: 10.1038/srep19108.
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.
细胞外嘌呤能产物，尤其是三磷酸腺苷（ATP），最近被认为可调节免疫细胞功能，并导致免疫疾病的异常炎症反应。然而，细胞外ATP及其主要受体P2×7对结肠炎免疫反应的调节作用仍有待阐明。在本研究中，我们通过给小鼠喂食4%硫酸葡聚糖钠（DSS）诱导小鼠结肠炎，并注意到在实验性结肠炎进展过程中结肠组织中细胞外ATP水平显著升高。用生胃酮（CBX）处理阻断ATP释放，或用ATP二磷酸水解酶（apyrase）促进ATP降解，可降低结肠组织中细胞外ATP水平，减轻DSS诱导的结肠炎，而用偏钨酸钠（POM-1）抑制细胞外ATP降解则会加重结肠炎小鼠的组织损伤。此外，用P2×7受体抑制剂A438079处理可降低固有层免疫细胞中NFκB的激活和活性半胱天冬酶-1的表达，下调结肠组织中促炎细胞因子的产生，并减轻小鼠结肠炎。总体而言，这些数据表明细胞外ATP通过P2×7受体、炎性小体和NFκB信号传导参与实验性结肠炎炎症反应的调节，这为目前抑制细胞外ATP介导的免疫反应性的临床方法提供了潜在的替代方案。
