Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology.
Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology.
复制标题
作者：
与IBD、牛皮癣和强直性脊柱炎相关的IL-23R易感等位基因的确定支持了IL-23在自身免疫性和慢性炎症性疾病发病机制中的关键作用。IL-23驱动的炎症主要与Th17细胞的活动有关。有些被忽视的是，IL-23对先天免疫细胞也有炎症作用，可以推动T细胞非依赖性结肠炎。然而，参与这种先天肠道炎症反应的下游细胞和分子通路尚不清楚。在这里，我们表明，细菌驱动的先天性结肠炎与结肠中IL-17和干扰素-γ的产生增加有关。IL-23刺激结肠白细胞可诱导表达Thy1、Sca-1、RoR-γ和IL-23R的固有淋巴样细胞产生IL-17和干扰素-γ，这些细胞明显聚集在炎症的结肠中。重要的是，对IL-23有反应的固有肠道细胞也是结肠炎T细胞依赖模型的一个特征。转录因子RoRγt控制IL-23R的表达，在RoR−/−RAG−/−小鼠未能发展为先天性结肠炎的情况下发挥作用。最后，去除Thy1+天然淋巴样细胞可完全消灭急、慢性先天性结肠炎。这些结果确定了一种新的IL-23反应性先天淋巴细胞群，它介导了肠道免疫病理，因此可能是IBD的靶点。
The key role of IL-23 in the pathogenesis of autoimmune and chronic inflammatory disorders is supported by the identification of IL-23R susceptibility alleles associated with IBD, psoriasis and ankylosing spondylitis. IL-23 driven inflammation has primarily been linked to the actions of Th17 cells. Somewhat overlooked, IL-23 also has inflammatory effects on innate immune cells and can drive T cell- independent colitis. However the downstream cellular and molecular pathways involved in this innate intestinal inflammatory response are poorly characterized. Here we show that bacteria-driven innate colitis is associated with increased IL-17 and IFN-γ production in the colon. Stimulation of colonic leukocytes with IL-23 induced IL-17 and IFN-γ production exclusively by innate lymphoid cells expressing Thy1, SCA-1, RORγt and IL-23R and these cells markedly accumulated in the inflamed colon. Importantly, IL-23 responsive innate intestinal cells are also a feature of T-cell dependent models of colitis. The transcription factor RORγt, which controls IL-23R expression, plays a functional role as Ror−/−Rag−/− mice failed to develop innate colitis. Lastly, depletion of Thy1+ innate lymphoid cells completely abrogated acute and chronic innate colitis. These results identify a novel IL-23 responsive innate lymphoid population that mediates intestinal immune pathology and may therefore represent a target in IBD.
登录
查看更多内容
影响因子：
64.5
作者：
Ivanov, Ivaylo I.;McKenzie, Brent S.;Littman, Dan R.
通讯作者：
Littman, Dan R.
影响因子：
64.8
作者：
Cella, Marina;Fuchs, Anja;Vermi, William;Facchetti, Fabio;Otero, Karel;Lennerz, Jochen K. M.;Doherty, Jason M.;Mills, Jason C.;Colonna, Marco
通讯作者：
Colonna, Marco
影响因子：
32.4
作者：
Veldhoen, M;Hocking, RJ;Stockinger, B
通讯作者：
Stockinger, B
影响因子：
32.4
作者：
Uhlig, Holm H.;McKenzie, Brent S.;Powrie, Fiona
通讯作者：
Powrie, Fiona
影响因子：
30.5
作者：
通讯作者：
--