The ATP-hydrolyzing ectoenzyme E-NTPD8 attenuates colitis through modulation of P2X4 receptor–dependent metabolism in myeloid cells

Significance Intestinal bacteria produce extracellular ATP in the lumen during their growth, which drives host immune responses. To avoid excessive immune reactions in the intestinal mucosa, luminal ATP is finely tuned. However, how the concentration of luminal ATP is controlled in the colon remains poorly understood. Here, we discovered that ATP-hydrolyzing enzyme E-NTPD8 acts as an immunomodulator in the colon. Entpd8 deficiency led to high sensitivity to DSS-induced colitis in mice, which was due to the sustained survival of colonic neutrophils. Extracellular ATP suppressed apoptosis by inducing metabolic alteration toward glycolysis via P2X4R in neutrophils. These results reveal the mechanism preventing innate intestinal pathology through modulation of myeloid cell metabolism and may serve to identify therapeutic targets for IBD.