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The development of colitis in Il10-/- mice is dependent on IL-22.
Mucosal Immunology ( IF 8 ) Pub Date : 2020-01-13 , DOI: 10.1038/s41385-019-0252-3
Dilini C Gunasekera 1 , Jinxia Ma 1 , Vimvara Vacharathit 2 , Palak Shah 1 , Amritha Ramakrishnan 1 , Priyanka Uprety 1 , Zeli Shen 3 , Alexander Sheh 3 , Cory F Brayton 4 , Mark T Whary 3 , James G Fox 3 , Jay H Bream 1, 2
Affiliation  

Mice deficient in the IL-10 pathway are the most widely used models of intestinal immunopathology. IL-17A is strongly implicated in gut disease in mice and humans, but conflicting evidence has drawn IL-17's role in the gut into question. IL-22 regulates antimicrobial and repair activities of intestinal epithelial cells (IECs) and is closely associated with IL-17A responses but it's role in chronic disease is uncertain. We report that IL-22, like IL-17A, is aberrantly expressed in colitic Il10-/- mice. While IL-22+ Th17 cells were elevated in the colon, IL-22-producing ILC3s were highly enriched in the small intestines of Il10-/- mice. Remarkably, Il10-/-Il22-/- mice did not develop colitis despite retaining high levels of Th17 cells and remaining colonized with colitogenic Helicobacter spp. Accordant with IL-22-induced IEC proliferation, the epithelia hyperplasia observed in Il10-/- animals was reversed in Il10-/-Il22-/- mice. Also, the high levels of antimicrobial IL-22-target genes, including Reg3g, were normalized in Il10-/-Il22-/- mice. Consistent with a heightened antimicrobial environment, Il10-/- mice had reduced diversity of the fecal microbiome that was reestablished in Il10-/-Il22-/- animals. These data suggest that spontaneous colitis in Il10-/- mice is driven by IL-22 and implicates an underappreciated IL-10/IL-22 axis in regulating intestinal homeostasis.

中文翻译:

Il10-/- 小鼠结肠炎的发展依赖于 IL-22。

IL-10 通路缺陷的小鼠是最广泛使用的肠道免疫病理学模型。IL-17A 与小鼠和人类的肠道疾病密切相关,但相互矛盾的证据使 IL-17 在肠道中的作用受到质疑。IL-22 调节肠上皮细胞 (IEC) 的抗菌和修复活性,并与 IL-17A 反应密切相关,但它在慢性疾病中的作用尚不确定。我们报告说,IL-22 与 IL-17A 一样,在结肠炎 Il10-/- 小鼠中异常表达。虽然 IL-22+ Th17 细胞在结肠中升高,但产生 IL-22 的 ILC3 在 Il10-/- 小鼠的小肠中高度富集。值得注意的是,Il10-/-Il22-/- 小鼠尽管保留了高水平的 Th17 细胞并仍被致结肠炎的螺杆菌定植,但并未发展为结肠炎。根据 IL-22 诱导的 IEC 增殖,在 Il10-/- 动物中观察到的上皮细胞增生在 Il10-/- Il22-/- 小鼠中得到逆转。此外,高水平的抗菌 IL-22 靶基因(包括 Reg3g)在 Il10-/-Il22-/- 小鼠中正常化。与增强的抗菌环境一致,Il10-/- 小鼠减少了粪便微生物组的多样性,而这些微生物组在 Il10-/-Il22-/- 动物中重建。这些数据表明 Il10-/- 小鼠的自发性结肠炎是由 IL-22 驱动的,并且暗示在调节肠道稳态中未被充分认识的 IL-10/IL-22 轴。Il10-/- 小鼠减少了粪便微生物组的多样性,该微生物组在 Il10-/-Il22-/- 动物中重建。这些数据表明 Il10-/- 小鼠的自发性结肠炎是由 IL-22 驱动的,并且暗示在调节肠道稳态中未被充分认识的 IL-10/IL-22 轴。Il10-/- 小鼠减少了粪便微生物组的多样性,该微生物组在 Il10-/-Il22-/- 动物中重建。这些数据表明 Il10-/- 小鼠的自发性结肠炎是由 IL-22 驱动的,并且暗示在调节肠道稳态中未被充分认识的 IL-10/IL-22 轴。
更新日期:2020-01-13
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