Department of Digestive Disease, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, 230001 Hefei, China.
Hefei National Laboratory for Physical Sciences at Microscale, the Chinese Academy of Sciences Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, 230027 Hefei, China.
Proc Natl Acad Sci U S A. 2021 Jan 26;118(4). doi: 10.1073/pnas.2017432118.
RNA helicases play roles in various essential biological processes such as RNA splicing and editing. Recent in vitro studies show that RNA helicases are involved in immune responses toward viruses, serving as viral RNA sensors or immune signaling adaptors. However, there is still a lack of in vivo data to support the tissue- or cell-specific function of RNA helicases owing to the lethality of mice with complete knockout of RNA helicases; further, there is a lack of evidence about the antibacterial role of helicases. Here, we investigated the in vivo role of Dhx15 in intestinal antibacterial responses by generating mice that were intestinal epithelial cell (IEC)-specific deficient for Dhx15 (Dhx15 f/f Villin1-cre, Dhx15). These mice are susceptible to infection with enteric bacteria (), owing to impaired α-defensin production by Paneth cells. Moreover, mice with Paneth cell-specific depletion of Dhx15 (Dhx15 f/f Defensinα6-cre, Dhx15) are more susceptible to DSS (dextran sodium sulfate)-induced colitis, which phenocopy Dhx15 mice, due to the dysbiosis of the intestinal microbiota. In humans, reduced protein levels of Dhx15 are found in ulcerative colitis (UC) patients. Taken together, our findings identify a key regulator of Wnt-induced α-defensins in Paneth cells and offer insights into its role in the antimicrobial response as well as intestinal inflammation.
RNA 解旋酶在 RNA 剪接和编辑等各种重要的生物学过程中发挥作用。最近的体外研究表明，RNA 解旋酶参与针对病毒的免疫反应，作为病毒 RNA 传感器或免疫信号适配器。然而，由于 RNA 解旋酶完全敲除的小鼠具有致死性，因此缺乏支持 RNA 解旋酶在组织或细胞特异性功能的体内数据；此外，缺乏关于解旋酶的抗菌作用的证据。在这里，我们通过生成肠道上皮细胞（IEC）特异性缺乏 Dhx15 的小鼠（Dhx15 f/f Villin1-cre，Dhx15）来研究 Dhx15 在肠道抗菌反应中的体内作用。由于 Paneth 细胞中 α-防御素的产生受损，这些小鼠易感染肠道细菌（）。此外，由于肠道微生物群落的失调，Paneth 细胞特异性缺失 Dhx15 的小鼠（Dhx15 f/f Defensinα6-cre，Dhx15）更容易发生 DSS（葡聚糖硫酸钠）诱导的结肠炎，这与 Dhx15 小鼠类似。在人类中，溃疡性结肠炎（UC）患者中 Dhx15 的蛋白水平降低。总之，我们的研究结果确定了 Paneth 细胞中 Wnt 诱导的α-防御素的关键调节剂，并深入了解了其在抗菌反应和肠道炎症中的作用。
