Protective mucosal immunity mediated by epithelial CD1d and IL-10.
Protective mucosal immunity mediated by epithelial CD1d and IL-10.
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DOI：
10.1038/nature13150
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发表时间：
2014-05-22
期刊：
影响因子：
64.8
通讯作者：
Blumberg, Richard S.
中科院分区：
文献类型：
--
作者：
Olszak, Torsten;Neves, Joana F.;Dowds, C. Marie;Baker, Kristi;Glickman, Jonathan;Davidson, Nicholas O.;Lin, Chyuan-Sheng;Jobin, Christian;Brand, Stephan;Sotlar, Karl;Wada, Koichiro;Katayama, Kazufumi;Nakajima, Atsushi;Mizuguchi, Hiroyuki;Kawasaki, Kunito;Nagata, Kazuhiro;Mueller, Werner;Snapper, Scott B.;Schreiber, Stefan;Kaser, Arthur;Zeissig, Sebastian;Blumberg, Richard S.
维持粘膜稳态的机制对炎症性肠病至关重要。这些过程的关键是肠上皮细胞（IEC），它调节肠道微生物群和宿主之间界面的免疫反应。CD 1d将自身和微生物脂质抗原呈递给自然杀伤T（NKT）细胞，其参与动物模型中的结肠炎和人类炎症性肠病的发病机制。由于模型IEC上的CD 1d交联导致产生重要的调节细胞因子白细胞介素（IL）-10（参考文献），在炎症性肠病中观察到的上皮CD 1d表达降低可能实质上导致肠道炎症。在这里，我们在小鼠中发现，骨髓来源的CD 1d信号有助于NKT细胞介导的肠道炎症，而上皮CD 1d通过激活STAT 3和IL-10，热休克蛋白110（HSP 110;也称为HSP 105）和CD 1d本身的STAT 3依赖性转录发挥保护作用。所有这些上皮成分都与控制CD 1d介导的肠道炎症密切相关。这通过IEC特异性缺失IL-10、CD 1d及其关键调节因子微粒体甘油三酯转移蛋白（MTP）以及放射抗性隔室中缺失HSP 110后的严重NKT细胞介导的结肠炎得到证实。因此，我们的研究揭示了IEC依赖性调节粘膜稳态的新途径，并强调了IL-10在肠上皮中的关键作用，对炎症性肠病等疾病具有广泛的意义。
The mechanisms by which mucosal homeostasis is maintained are of central importance to inflammatory bowel disease. Critical to these processes is the intestinal epithelial cell (IEC), which regulates immune responses at the interface between the commensal microbiota and the host. CD1d presents self and microbial lipid antigens to natural killer T (NKT) cells, which are involved in the pathogenesis of colitis in animal models and human inflammatory bowel disease. As CD1d crosslinking on model IECs results in the production of the important regulatory cytokine interleukin (IL)-10 (ref.), decreased epithelial CD1d expression—as observed in inflammatory bowel disease—may contribute substantially to intestinal inflammation. Here we show in mice that whereas bone-marrow-derived CD1d signals contribute to NKT-cell-mediated intestinal inflammation, engagement of epithelial CD1d elicits protective effects through the activation of STAT3 and STAT3-dependent transcription of IL-10, heat shock protein 110 (HSP110; also known as HSP105), and CD1d itself. All of these epithelial elements are critically involved in controlling CD1d-mediated intestinal inflammation. This is demonstrated by severe NKT-cell-mediated colitis upon IEC-specific deletion of IL-10, CD1d, and its critical regulator microsomal triglyceride transfer protein (MTP), as well as deletion of HSP110 in the radioresistant compartment. Our studies thus uncover a novel pathway of IEC-dependent regulation of mucosal homeostasis and highlight a critical role of IL-10 in the intestinal epithelium, with broad implications for diseases such as inflammatory bowel disease.
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DOI：
10.1126/science.1219328
发表时间：
2012-04-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Olszak T;An D;Zeissig S;Vera MP;Richter J;Franke A;Glickman JN;Siebert R;Baron RM;Kasper DL;Blumberg RS
通讯作者：
Blumberg RS
影响因子：
15.9
作者：
Colgan, SP;Pitman, RS;Blumberg, RS
通讯作者：
Blumberg, RS
影响因子：
8.7
作者：
Saenz SA;Taylor BC;Artis D
通讯作者：
Artis D
DOI：
10.1084/jem.20082683
发表时间：
2009-07-06
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Pickert G;Neufert C;Leppkes M;Zheng Y;Wittkopf N;Warntjen M;Lehr HA;Hirth S;Weigmann B;Wirtz S;Ouyang W;Neurath MF;Becker C
通讯作者：
Becker C
影响因子：
29.7
作者：
Kaser A;Zeissig S;Blumberg RS
通讯作者：
Blumberg RS