Erbin exerts a protective effect against inflammatory bowel disease by suppressing autophagic cell death.
Erbin exerts a protective effect against inflammatory bowel disease by suppressing autophagic cell death.
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DOI：
10.18632/oncotarget.23925
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发表时间：
2018-02-23
期刊：
影响因子：
--
通讯作者：
Li JM
中科院分区：
文献类型：
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作者：
Shen T;Li S;Cai LD;Liu JL;Wang CY;Gan WJ;Li XM;Wang JR;Sun LN;Deng M;Liu YH;Li JM
包括克罗恩病（CD）和溃疡性结肠炎（UC）在内的炎症性肠病（IBD）的发病机制和关键功能分子仍不清楚。在这里，我们报道了 Erbin 是一种上皮细胞极性所需的蛋白质，在物种之间是保守的，并且在小鼠和斑马鱼的肠粘膜中高度表达。病理学上，DSS诱导的急性结肠炎小鼠、IL-10缺陷小鼠和溃疡性结肠炎患者的临床活检标本中肠粘膜中的Erbin表达显着降低。此外，Erbin缺陷小鼠更容易患实验性结肠炎，表现出更严重的肠道屏障破坏，组织学评分增加和促炎细胞因子产生过多。从机制上讲，Erbin 缺乏或敲低显着加剧了体内和体外自噬程序的激活和自噬细胞死亡。而且，氯喹抑制自噬可减轻 DSS 诱导的 Erbin 缺失结肠炎小鼠模型中的过度炎症反应。总的来说，我们的研究揭示了 Erbin 在自噬细胞死亡和 IBD 中的关键作用，通过抑制自噬的过度激活和自噬细胞死亡，提出了 IBD 治疗的新策略。
The pathogenesis and key functional molecules involved in inflammatory bowel disease (IBD) including Crohn's disease (CD) and ulcerative colitis (UC) remain unclear. Here, we reported that Erbin, a protein required for the polarity of epithelial cells, is conserved across species and highly expressed in the intestinal mucosa in mice and zebrafish. Pathologically, Erbin expression in the intestinal mucosa was significantly decreased in DSS induced acute colitis mice, IL-10 deficient mice and clinical biopsy specimens from patients with ulcerative colitis. Moreover, Erbin deficient mice are more susceptible to experimental colitis, exhibiting more severe intestinal barrier disruption, with increased histological scores and excessive production of proinflammatory cytokines. Mechanistically, Erbin deficiency or knockdown significantly exacerbated activation of autophagic program and autophagic cell death in vivo and in vitro. And, inhibition of autophagy by Chloroquine attenuates excessive inflammatory response in the DSS-induced colitis mouse model of Erbin deletion. Generally, our study uncovers a crucial role of Erbin in autophagic cell death and IBD, giving rise to a new strategy for IBD therapy by inhibiting excessive activation of autophagy and autophagic cell death.