I. Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, 20246 Hamburg, Germany.
Microbial Immune Regulation Research Group, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.
J Immunol. 2018 Dec 15;201(12):3558-3568. doi: 10.4049/jimmunol.1800711. Epub 2018 Nov 16.
Inflammatory bowel disease is associated with extraintestinal diseases such as primary sclerosing cholangitis in the liver. Interestingly, it is known that an imbalance between Foxp3 regulatory T cells (Treg) and Th17 cells is involved in inflammatory bowel disease and also in primary sclerosing cholangitis. To explain these associations, one hypothesis is that intestinal inflammation and barrier defects promote liver disease because of the influx of bacteria and inflammatory cells to the liver. However, whether and how this is linked to the Treg and Th17 cell imbalance is unclear. To address this, we used dextran sodium sulfate (DSS) and T cell transfer colitis mouse models. We analyzed the pathological conditions of the intestine and liver on histological, cellular, and molecular levels. We observed bacterial translocation and an influx of inflammatory cells, in particular Th17 cells, to the liver during colitis. In the DSS colitis model, in which Treg were concomitantly increased in the liver, we did not observe an overt pathological condition of the liver. In contrast, the T cell-mediated colitis model, in which Treg are not abundant, was associated with marked liver inflammation and a pathological condition. Of note, upon depletion of Treg in DEREG mice, DSS colitis promotes accumulation of Th17 cells and a pathological condition of the liver. Finally, we studied immune cell migration using KAEDE mice and found that some of these cells had migrated directly from the inflamed intestine into the liver. Overall, these data indicate that colitis can promote a pathological condition of the liver and highlight an important role of Treg in controlling colitis-associated liver inflammation.
炎症性肠病与肝脏原发性硬化性胆管炎等肠外疾病有关。有趣的是，已知 Foxp3 调节性 T 细胞（Treg）与 Th17 细胞之间的失衡与炎症性肠病和原发性硬化性胆管炎有关。为了解释这些关联，有一种假设是肠道炎症和屏障缺陷会促进肝脏疾病的发生，因为细菌和炎症细胞会涌入肝脏。然而，这种情况是否以及如何与 Treg 和 Th17 细胞失衡有关尚不清楚。为了解决这个问题，我们使用了葡聚糖硫酸钠（DSS）和 T 细胞转移结肠炎小鼠模型。我们在组织学、细胞和分子水平上分析了肠道和肝脏的病理状况。我们观察到在结肠炎期间细菌易位和炎症细胞，特别是 Th17 细胞，涌入肝脏。在 DSS 结肠炎模型中，Treg 同时在肝脏中增加，我们没有观察到肝脏的明显病理状况。相比之下，在 T 细胞介导的结肠炎模型中，Treg 不丰富，与明显的肝脏炎症和病理状况相关。值得注意的是，在 DEREG 小鼠中耗尽 Treg 后，DSS 结肠炎促进了 Th17 细胞的积累和肝脏的病理状况。最后，我们使用 KAEDE 小鼠研究了免疫细胞的迁移，发现其中一些细胞已经从发炎的肠道直接迁移到肝脏。总体而言，这些数据表明结肠炎可以促进肝脏的病理状况，并强调了 Treg 在控制结肠炎相关的肝脏炎症中的重要作用。
