Laboratory of Host Defense, The World Premier International Research Center Initiative (WPI) Immunology Frontier Research Center, Osaka University, 565-0871 Osaka, Japan.
Fujii Memorial Research Institute, Otsuka Pharmaceutical Company, Ltd., 520-0106 Shiga, Japan.
Proc Natl Acad Sci U S A. 2018 Oct 23;115(43):11036-11041. doi: 10.1073/pnas.1809575115. Epub 2018 Oct 8.
Damage to intestinal epithelial cell (IEC) layers during intestinal inflammation is associated with inflammatory bowel disease. Here we show that the endoribonuclease Regnase-1 controls colon epithelial regeneration by regulating protein kinase mTOR (the mechanistic target of rapamycin kinase) and purine metabolism. During dextran sulfate sodium-induced intestinal epithelial injury and acute colitis, Regnase-1 mice, which lack Regnase-1 specifically in the intestinal epithelium, were resistant to body weight loss, maintained an intact intestinal barrier, and showed increased cell proliferation and decreased epithelial apoptosis. Chronic colitis and tumor progression were also attenuated in Regnase-1 mice. Regnase-1 predominantly regulates mTORC1 signaling. Metabolic analysis revealed that Regnase-1 participates in purine metabolism and energy metabolism during inflammation. Furthermore, increased expression of ectonucleotidases contributed to the resolution of acute inflammation in Regnase-1 mice. These findings provide evidence that Regnase-1 deficiency has beneficial effects on the prevention and/or blocking of intestinal inflammatory disorders.
肠道炎症期间肠上皮细胞 (IEC) 层的损伤与炎症性肠病有关。在这里，我们表明内切核糖核酸酶 Regnase-1 通过调节蛋白激酶 mTOR（雷帕霉素激酶的机制靶点）和嘌呤代谢来控制结肠上皮细胞的再生。在葡聚糖硫酸钠诱导的肠上皮损伤和急性结肠炎期间，特异性缺乏肠道上皮细胞中 Regnase-1 的 Regnase-1 小鼠抵抗体重减轻，维持完整的肠屏障，并显示出增加的细胞增殖和减少的上皮细胞凋亡。Regnase-1 小鼠的慢性结肠炎和肿瘤进展也减弱。Regnase-1 主要调节 mTORC1 信号。代谢分析表明，Regnase-1 在炎症过程中参与嘌呤代谢和能量代谢。此外，增加的外核苷酸酶的表达有助于 Regnase-1 小鼠急性炎症的消退。这些发现为 Regnase-1 缺乏对预防和/或阻断肠道炎症性疾病具有有益作用提供了证据。
