Sato Tatsuhiro, To Keii, Sakurai Fumika, Chihara Kanako, Warabi Eiji, Isobe Tomonori, Suzuki Hideo, Shoda Junichi, Okada Kosuke
Doctoral Program in Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan.
Green Clinic, 2215 Yaita, Tsukubamirai-shi, Ibaraki 300-2337, Japan.
Exp Anim. 2025 Jul 11;74(3):335-347. doi: 10.1538/expanim.24-0152. Epub 2025 Jan 25.
Unbalanced redox homeostasis leads to the production of reactive oxygen species and exacerbates inflammatory bowel disease. To investigate the role of the transcription factor Nrf2, a major antioxidative stress sensor, in intestinal epithelial cells (IECs), we generated IEC-specific Nrf2 gene knock-in mice (Nrf2-vRes), which express Nrf2 only in IECs, using the cre/loxp system. Colitis was induced in wild-type (WT) mice, whole-body Nrf2-knockout (Nrf2-KO) mice, and Nrf2-vRes mice by administering dextran sulfate sodium (DSS) for 1 week (acute model) or intermittently for 5 weeks (chronic model). The mRNA and protein levels of NAD(P)H:quinone oxidoreductase 1 (NQO1), which is involved in the oxidative stress response in a manner regulated by Nrf2, were reduced in Nrf2-KO compared with those in WT, while these decreases were reversed in Nrf2-vRes at all timepoints. Nrf2-KO mice administered DSS developed more severe colitis with higher disease activity index, higher leucine-rich α2 glycoprotein in serum, shorter colon length, and more severe epithelial damage and infiltration of inflammatory cells histopathologically than did WT mice in the acute model; moreover, these exacerbations of colitis were ameliorated in Nrf2-vRes mice. However, these differences were not observed among the three sets of mice in the chronic model. IEC-specific expression of Nrf2 ameliorated DSS-induced acute colitis. These results suggest that Nrf2 expression in IECs plays a protective role against early-stage colitis and undertakes important regulatory functions during intestinal inflammation.
氧化还原稳态失衡会导致活性氧的产生，并加剧炎症性肠病。为了研究转录因子Nrf2（一种主要的抗氧化应激传感器）在肠上皮细胞（IECs）中的作用，我们使用cre/loxp系统构建了IEC特异性Nrf2基因敲入小鼠（Nrf2-vRes），其仅在IECs中表达Nrf2。通过给予硫酸葡聚糖钠（DSS）1周（急性模型）或间歇性给予5周（慢性模型），在野生型（WT）小鼠、全身Nrf2基因敲除（Nrf2-KO）小鼠和Nrf2-vRes小鼠中诱导结肠炎。Nrf2以一种受其调控的方式参与氧化应激反应，与WT小鼠相比，Nrf2-KO小鼠中参与氧化应激反应的NAD(P)H：醌氧化还原酶1（NQO1）的mRNA和蛋白水平降低，而在所有时间点，Nrf2-vRes小鼠中的这些降低均得到逆转。在急性模型中，给予DSS的Nrf2-KO小鼠发生了更严重的结肠炎，疾病活动指数更高，血清中富含亮氨酸的α2糖蛋白水平更高，结肠长度更短，并且在组织病理学上上皮损伤和炎症细胞浸润比WT小鼠更严重；此外，Nrf2-vRes小鼠中结肠炎的这些加重情况得到改善。然而，在慢性模型的三组小鼠中未观察到这些差异。IEC特异性表达Nrf2可改善DSS诱导的急性结肠炎。这些结果表明，IECs中Nrf2的表达对早期结肠炎起保护作用，并在肠道炎症期间发挥重要的调节功能。
