Extracellular adenosine triphosphate (ATP) released by mucosal immune cells and by microbiota in the intestinal lumen elicits diverse immune responses that mediate the intestinal homeostasis via P2 purinergic receptors, while overactivation of ATP signaling leads to mucosal immune system disruption, which leads to pathogenesis of intestinal inflammation. In the small intestine, hydrolysis of luminal ATP by ectonucleoside triphosphate diphosphohydrolase (E-NTPD)7 in epithelial cells is essential for control of the number of T helper 17 (Th17) cells. However, the molecular mechanism by which microbiota-derived ATP in the colon is regulated remains poorly understood. Here, we show that E-NTPD8 is highly expressed in large-intestinal epithelial cells and hydrolyzes microbiota-derived luminal ATP. Compared with wild-type mice, Entpd8^−/− mice develop more severe dextran sodium sulfate–induced colitis, which can be ameliorated by either the depletion of neutrophils and monocytes by injecting with anti–Gr-1 antibody or the introduction of P2rx4 deficiency into hematopoietic cells. An increased level of luminal ATP in the colon of Entpd8^−/− mice promotes glycolysis in neutrophils through P2x4 receptor–dependent Ca²⁺ influx, which is linked to prolonged survival and elevated reactive oxygen species production in these cells. Thus, E-NTPD8 limits intestinal inflammation by controlling metabolic alteration toward glycolysis via the P2X4 receptor in myeloid cells.

粘膜免疫细胞和肠腔微生物群释放的胞外三磷酸腺苷 (ATP) 引发多种免疫反应，通过 P2 嘌呤能受体介导肠道稳态，而 ATP 信号的过度激活导致粘膜免疫系统破坏，从而导致肠道疾病的发生。炎。在小肠中，上皮细胞中外核苷三磷酸二磷酸水解酶 (E-NTPD)7 对管腔 ATP 的水解对于控制 T 辅助 17 (Th17) 细胞的数量至关重要。然而，对结肠中微生物群衍生的 ATP 进行调节的分子机制仍知之甚少。在这里，我们表明 E-NTPD8 在大肠上皮细胞中高度表达并水解微生物群衍生的管腔 ATP。与野生型小鼠相比，Entpd8 ^-/-小鼠会发生更严重的葡聚糖硫酸钠诱导的结肠炎，这可以通过注射抗 Gr-1 抗体消耗中性粒细胞和单核细胞或将P2rx4缺陷引入造血细胞来改善。Entpd8 ^-/-小鼠结肠中增加的管腔 ATP 水平通过依赖 P2x4 受体的 Ca ²⁺流入促进中性粒细胞的糖酵解，这与这些细胞中存活时间延长和活性氧产生增加有关。因此，E-NTPD8 通过骨髓细胞中的 P2X4 受体控制代谢改变向糖酵解，从而限制肠道炎症。