Department of Biological Sciences, University of South Carolina, 715 Sumter St., Columbia, SC 29208, USA.
Department of Biological Sciences, University of South Carolina, 715 Sumter St., Columbia, SC 29208, USA.
Differentiation. 2018 Jan-Feb;99:51-61. doi: 10.1016/j.diff.2017.12.003. Epub 2017 Dec 15.
Maintenance of the intestinal mucosa is driven by local signals that coordinate epithelial proliferation, differentiation, and turnover in order to separate antigenic luminal contents from the host's immune system. Breaches in this barrier promote gastrointestinal pathologies ranging from inflammatory bowel disease to cancer. The ubiquitin ligase ITCH is known to regulate immune responses, and loss of function of ITCH has been associated with gastrointestinal inflammatory disorders, particularly in the colon. However, the small intestine appears to be spared from this pathology. Here we explored the physiological mechanism that underlies the preservation of mucosal homeostasis in the small intestine in mice lacking ITCH (Itch). Histological analysis of the small intestines from young adult mice revealed architectural changes in animals deficient for ITCH, including villus blunting with cell crowding, crypt expansion, and thickening of the muscularis propria relative to age-matched mice sufficient for ITCH. These differences were more prominent in the distal part of the small intestine and were not dependent upon lymphoid cells. Underlying the observed changes in the epithelium were expansion of the Ki67 proliferating transit amplifying progenitor population and increased numbers of terminally differentiated mucus-secreting goblet and anti-microbial producing Paneth cells, which are both important in controlling local inflammation in the small intestine and are known to be dysregulated in inflammatory bowel disease. Homeostasis in the small intestine of Itch animals was maintained by increased cell turnover, including accelerated migration of epithelial cells along the crypt-villus axis and increased apoptosis of epithelial cells at the crypt-villus junction. Consistent with this enhanced turnover, Itch mice carrying the Min mutation (Itch; Apc) displayed a 76% reduction in tumor burden as compared to Apc littermates with normal levels of ITCH. These findings highlight the role of ITCH as an important modulator of intestinal epithelial homeostasis.
肠道黏膜的维持依赖于局部信号，这些信号协调上皮细胞的增殖、分化和更替，以便将腔内抗原性内容物与宿主的免疫系统隔离开来。这种屏障的破坏会促进从炎症性肠病到癌症等各种胃肠道疾病的发生。已知泛素连接酶 ITCH 可调节免疫反应，ITCH 功能丧失与胃肠道炎症性疾病有关，特别是在结肠中。然而，小肠似乎免受这种病理的影响。在这里，我们研究了缺乏 ITCH（ITCH）的小鼠（Itch）中维持小肠黏膜稳态的生理机制。对幼年小鼠小肠的组织学分析显示，ITCH 缺乏的动物存在结构变化，包括绒毛变钝、细胞拥挤、隐窝扩张以及与具有足够 ITCH 的年龄匹配的小鼠相比固有肌层变厚。这些差异在小肠的远端更为明显，并且不依赖于淋巴细胞。在观察到的上皮变化的背后，是 Ki67 增殖过渡扩增祖细胞群体的扩张以及终末分化的分泌粘液的 goblet 细胞和产生抗菌物质的 Paneth 细胞数量的增加，这两者在控制小肠局部炎症中都很重要，并且已知在炎症性肠病中失调。ITCH 动物的小肠稳态通过增加细胞更替来维持，包括沿着隐窝-绒毛轴上皮细胞的加速迁移和隐窝-绒毛交界处上皮细胞的凋亡增加。与这种增强的更替一致，携带 Min 突变（ITCH；Apc）的 ITCH 小鼠与具有正常 ITCH 水平的 Apc 同窝仔相比，肿瘤负担减少了 76%。这些发现强调了 ITCH 作为肠道上皮细胞稳态重要调节剂的作用。
