The ubiquitin ligase ITCH coordinates small intestinal epithelial homeostasis by modulating cell proliferation, differentiation, and migration.
The ubiquitin ligase ITCH coordinates small intestinal epithelial homeostasis by modulating cell proliferation, differentiation, and migration.
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DOI：
10.1016/j.diff.2017.12.003
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发表时间：
2018-01
期刊：
影响因子：
--
通讯作者：
Matesic LE
中科院分区：
文献类型：
--
作者：
Mentrup HL;Hartman A;Thames EL;Basheer WA;Matesic LE
肠粘膜的维持是由局部信号驱动的，这些信号协调上皮的增殖、分化和周转，以便将抗原腔内容物从宿主的免疫系统中分离出来。这一屏障的突破促进了从炎症性肠病到癌症的各种胃肠道病理。已知泛素连接酶瘙痒可以调节免疫反应，瘙痒功能的丧失与胃肠道炎症疾病有关，特别是在结肠。然而，小肠似乎没有受到这种病理影响。在这里，我们探索了在缺乏瘙痒的小鼠(Itcha18H/a18H)的小肠中保持粘膜动态平衡的生理机制。对幼年成年小鼠小肠的组织学分析显示，在缺乏瘙痒的动物中，结构发生了变化，包括绒毛变钝，细胞拥挤，隐窝扩张，固有肌增厚，相对于有足够瘙痒症状的年龄匹配的小鼠。这些差异在小肠的远端更为显著，不依赖于淋巴样细胞。在观察到的上皮变化的基础上，Ki67+增殖性转运扩增祖细胞群体的扩张，以及终末分化的粘液分泌杯和产生抗微生物的Paneth细胞数量的增加，这两种细胞在控制小肠局部炎症方面都很重要，并且已知在炎症性肠病中调节失调。Itcha18H/a18H动物小肠的动态平衡是通过增加细胞周转率来维持的，包括上皮细胞沿隐窝-绒毛轴的加速迁移和隐窝-绒毛交界处上皮细胞的凋亡增加。与这种增强的周转一致，携带Min突变(Itcha18H/a18H；ApcMin/+)的Itcha18H/a18H小鼠与瘙痒水平正常的ApcMin/+小鼠相比，肿瘤负担减少了76%。这些发现突显了瘙痒作为肠上皮内稳态的重要调节器的作用。
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 (Itcha18H/a18H). 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 Itcha18H/a18H 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, Itcha18H/a18H mice carrying the Min mutation (Itcha18H/a18H; ApcMin/+) displayed a 76% reduction in tumor burden as compared to ApcMin/+ littermates with normal levels of ITCH. These findings highlight the role of ITCH as an important modulator of intestinal epithelial homeostasis.
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DOI：
10.1038/nri.2016.88
发表时间：
2016-10
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Johansson ME;Hansson GC
通讯作者：
Hansson GC
影响因子：
2.4
作者：
Bischoff SC;Barbara G;Buurman W;Ockhuizen T;Schulzke JD;Serino M;Tilg H;Watson A;Wells JM
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影响因子：
15.9
作者：
Jin, Hyung-Seung;Park, Yoon;Liu, Yun-Cai
通讯作者：
Liu, Yun-Cai
影响因子：
1.6
作者：
Grimelius, L
通讯作者：
Grimelius, L
影响因子：
2.9
作者：
Gersemann, Michael;Becker, Svetlana;Stange, Eduard Friedrich
通讯作者：
Stange, Eduard Friedrich