Innate immunity contributes to the pathogenesis of inflammatory bowel disease (IBD). However, the mechanisms of IBD mediated by innate immunity are incompletely understood and there are limited models of spontaneous innate immune colitis to address this question. Here we describe a new robust model of colitis occurring in the absence of adaptive immunity. RAG1-deficient mice expressing TNFAIP3 in intestinal epithelial cells (TRAG mice) spontaneously developed 100% penetrant, early-onset colitis that was limited to the colon and dependent on intestinal microbes but was not transmissible to co-housed littermates. TRAG colitis was associated with increased mucosal numbers of innate lymphoid cells (ILCs) and depletion of ILC prevented colitis in TRAG mice. ILC depletion also therapeutically reversed established colitis in TRAG mice. The colitis in TRAG mice was not prevented by interbreeding to mice lacking group 3 ILC nor by depletion of TNF. Treatment with the JAK inhibitor ruxolitinib ameliorated colitis in TRAG mice. This new model of colitis, with its predictable onset and colon-specific inflammation, will have direct utility in developing a more complete understanding of innate immune mechanisms that can contribute to colitis and in pre-clinical studies for effects of therapeutic agents on innate immune-mediated IBD.

中文翻译：

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JAK 抑制剂 ruxolitinib 可减少 ILC3 非依赖性先天免疫性结肠炎模型中的炎症。

先天免疫有助于炎症性肠病 (IBD) 的发病机制。然而，先天免疫介导的 IBD 机制尚不完全清楚，而且自发性先天免疫性结肠炎模型有限，无法解决这个问题。在这里，我们描述了一种在没有适应性免疫的情况下发生的新的强大结肠炎模型。在肠上皮细胞（TRAG 小鼠）中表达 TNFAIP3 的 RAG1 缺陷小鼠自发地发展为 100% 渗透性早发性结肠炎，该结肠炎仅限于结肠并依赖于肠道微生物，但不会传染给共同饲养的同窝仔畜。TRAG 结肠炎与先天淋巴样细胞 (ILC) 粘膜数量增加有关，ILC 的消耗可预防 TRAG 小鼠的结肠炎。ILC 耗竭还在治疗上逆转了 TRAG 小鼠中已建立的结肠炎。TRAG 小鼠的结肠炎不能通过与缺乏第 3 组 ILC 的小鼠杂交或通过耗尽 TNF 来预防。用 JAK 抑制剂 ruxolitinib 治疗可改善 TRAG 小鼠的结肠炎。这种新的结肠炎模型具有可预测的发病和结肠特异性炎症，将直接用于更全面地了解可能导致结肠炎的先天免疫机制，以及治疗药物对先天免疫的影响的临床前研究。介导的 IBD。