2nd Department of Internal Medicine, Osaka Medical College, Daigakumachi, Takatsuki, Osaka, Japan.
Department of Pharmacology, Faculty of Medicine, Osaka Medical College, Daigakumachi, Takatsuki, Osaka, Japan.
PLoS One. 2019 Nov 8;14(11):e0225066. doi: 10.1371/journal.pone.0225066. eCollection 2019.
Autophagy is an essential process involved in the pathogenesis of inflammatory bowel disease (IBD). Although there are many data showing the roles of autophagy in intestinal epithelial cells (IECs), the mechanisms involved remain to be fully elucidated. We investigated the influence of autophagy in IECs on gastrointestinal tract inflammation.
Mice with conditional knockout of Atg5 in IECs (Atg5flox/flox/villin-Cre mice) were subjected to dextran sulfate sodium (DSS)-induced colitis and analyzed for colitis susceptibility. Additionally, we used Atg5-silenced rat IECs (IEC6shAtg5 cells) for in vitro assays.
Sensitivity to DSS markedly increased in Atg5flox/flox/villin-Cre mice compared to that in wild-type mice. In IEC6shAtg5 cells, apoptosis was enhanced, and cell viability significantly decreased compared to IEC-6 cells. The expression of proinflammatory cytokines increased upon suppression of autophagy. Furthermore, silencing of Atg5 was associated with inflammation of IECs, activation of the mitogen-activated protein kinase (MAPK) signaling pathway by the intracellular reactive oxygen species accumulation, and NF-κB p65 phosphorylation.
Autophagy in IECs plays an essential role in the maintenance of intestinal homeostasis, and autophagy deficiency triggers inflammation. Development of methods targeting autophagy might be beneficial in the treatment of IBD.
自噬是炎症性肠病（IBD）发病机制中涉及的一个重要过程。尽管有许多数据表明自噬在肠上皮细胞（IECs）中的作用，但涉及的机制仍有待充分阐明。我们研究了 IEC 中自噬对胃肠道炎症的影响。
用条件敲除 Atg5 的 IEC（Atg5flox/flox/villin-Cre 小鼠）进行葡聚糖硫酸钠（DSS）诱导的结肠炎，并分析结肠炎易感性。此外，我们使用 Atg5 沉默的大鼠 IEC（IEC6shAtg5 细胞）进行体外测定。
与野生型小鼠相比，Atg5flox/flox/villin-Cre 小鼠对 DSS 的敏感性明显增加。在 IEC6shAtg5 细胞中，与 IEC-6 细胞相比，细胞凋亡增强，细胞活力显著降低。自噬抑制后促炎细胞因子的表达增加。此外，Atg5 的沉默与 IEC 的炎症、细胞内活性氧积累引起的丝裂原活化蛋白激酶（MAPK）信号通路的激活以及 NF-κB p65 磷酸化有关。
IEC 中的自噬在维持肠道内稳态中起着重要作用，自噬缺乏会引发炎症。开发针对自噬的方法可能有益于 IBD 的治疗。
