Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan; Department for Medical Innovation and Translational Medical Science, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
Department of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, Yamagata 990-9585, Japan.
Free Radic Biol Med. 2019 Apr;134:153-164. doi: 10.1016/j.freeradbiomed.2018.12.024. Epub 2018 Dec 19.
Peroxiredoxin 4 (PRDX4), a secretory protein that is preferentially retained in the endoplasmic reticulum (ER), is encoded by a gene located on the X chromosome and highly expressed in colonic tissue. In this study, we investigated the role of PRDX4 by means of male PRDX4-knockout (PRDX4) mice in the development of intestinal inflammation using a dextran sulfate sodium (DSS)-induced colitis model.
Acute colitis was induced with DSS (2.5% in drinking water) in wild-type (WT) and PRDX4 male C57BL/6 mice. Histological and biochemical analyses were performed on the colonic tissues.
PRDX4 was mainly localized in the colonic epithelial cells in WT mice. The disease activity index (DAI) scores of PRDX4 mice were significantly higher compared to those of WT mice. Specifically, PRDX4 mice showed marked body weight loss and shortening of colon length compared to WT mice, whereas the myeloperoxidase levels were increased in PRDX4 compared to WT mice. In addition, the mRNA expression levels of TNF-α and IFN-γ were significantly higher in the colonic mucosa of PRDX4 compared to WT mice. Moreover, the levels of CHOP and activated caspase 3 were higher in the colonic tissues of PRDX4 compared to WT mice following treatment with DSS. The ER also showed greater expansion in PRDX4 than WT mice, which was consistent with severe ER stress under PRDX4 deficiency.
Our results demonstrated that the lack of PRDX4 aggravated the colonic mucosal damage induced by DSS. Because PRDX4 functions as an ER thiol oxidase as well as an antioxidant, DSS induced oxidative damage and ER stress to a greater degree in PRDX4 than WT mice. These findings suggest that PRDX4 may represent a novel therapeutic molecule in intestinal inflammation.
过氧化物酶 4（PRDX4）是一种优先保留在内质网（ER）中的分泌蛋白，由位于 X 染色体上的基因编码，在结肠组织中高度表达。在这项研究中，我们使用葡聚糖硫酸钠（DSS）诱导的结肠炎模型，通过雄性 PRDX4 敲除（PRDX4）小鼠来研究 PRDX4 的作用。
在野生型（WT）和 PRDX4 雄性 C57BL/6 小鼠的饮用水中加入 2.5%的 DSS 诱导急性结肠炎。对结肠组织进行组织学和生化分析。
PRDX4 在 WT 小鼠的结肠上皮细胞中主要定位。PRDX4 小鼠的疾病活动指数（DAI）评分明显高于 WT 小鼠。具体来说，与 WT 小鼠相比，PRDX4 小鼠表现出明显的体重减轻和结肠缩短，而髓过氧化物酶水平在 PRDX4 小鼠中升高。此外，PRDX4 小鼠结肠黏膜中 TNF-α和 IFN-γ的 mRNA 表达水平明显高于 WT 小鼠。此外，与 WT 小鼠相比，PRDX4 小鼠的 CHOP 和活化的 caspase 3 水平在 DSS 处理后更高。内质网在 PRDX4 小鼠中也显示出更大的扩张，这与 PRDX4 缺乏时严重的内质网应激一致。
我们的结果表明，PRDX4 的缺乏加剧了 DSS 诱导的结肠黏膜损伤。由于 PRDX4 作为 ER 硫醇氧化酶和抗氧化剂发挥作用，DSS 诱导的氧化损伤和 ER 应激在 PRDX4 小鼠中比 WT 小鼠更为严重。这些发现表明 PRDX4 可能是肠道炎症的一种新的治疗分子。
