Department of Cell and Molecular Biology, Karolinska Institute, SE-171 77 Solna, Stockholm, Sweden.
Department of Cell Biology, Faculty of Science, Charles University, Viničná 7, 128 00, Prague 2, Czech Republic.
EMBO Mol Med. 2024 Nov;16(11):2946-2975. doi: 10.1038/s44321-024-00145-8. Epub 2024 Oct 2.
Fibrosis contributes to tissue repair, but excessive fibrosis disrupts organ function. Alagille syndrome (ALGS, caused by mutations in JAGGED1) results in liver disease and characteristic fibrosis. Here, we show that Jag1 mice, a model for ALGS, recapitulate ALGS-like fibrosis. Single-cell RNA-seq and multi-color flow cytometry of the liver revealed immature hepatocytes and paradoxically low intrahepatic T cell infiltration despite cholestasis in Jag1 mice. Thymic and splenic regulatory T cells (Tregs) were enriched and Jag1 lymphocyte immune and fibrotic capacity was tested with adoptive transfer into Rag1 mice, challenged with dextran sulfate sodium (DSS) or bile duct ligation (BDL). Transplanted Jag1 lymphocytes were less inflammatory with fewer activated T cells than Jag1 lymphocytes in response to DSS. Cholestasis induced by BDL in Rag1 mice with Jag1 lymphocytes resulted in periportal Treg accumulation and three-fold less periportal fibrosis than in Rag1 mice with Jag1 lymphocytes. Finally, the Jag1 hepatocyte expression profile and Treg overrepresentation were corroborated in patients' liver samples. Jag1-dependent hepatic and immune defects thus interact to determine the fibrotic process in ALGS.
纤维化有助于组织修复，但过度纤维化会破坏器官功能。Alagille 综合征（由 JAGGED1 基因突变引起）导致肝脏疾病和特征性纤维化。在这里，我们展示了 Jag1 小鼠，一种 ALGS 的模型，重现了类似于 ALGS 的纤维化。肝脏的单细胞 RNA-seq 和多色流式细胞术显示，Jag1 小鼠尽管有胆汁淤积，但仍存在不成熟的肝细胞和异常低的肝内 T 细胞浸润。胸腺和脾脏调节性 T 细胞（Tregs）丰富，并通过向 Rag1 小鼠过继转移 Jag1 淋巴细胞来测试 Jag1 淋巴细胞的免疫和纤维化能力，该 Rag1 小鼠受到葡聚糖硫酸钠（DSS）或胆管结扎（BDL）的挑战。与 DSS 反应的 Jag1 淋巴细胞相比，移植的 Jag1 淋巴细胞炎症反应较少，活化 T 细胞较少。在 Rag1 小鼠中，BDL 诱导的胆汁淤积导致门静脉周围 Treg 积聚和门静脉周围纤维化减少三倍，而在 Rag1 小鼠中，Jag1 淋巴细胞的纤维化增加。最后，在患者的肝组织样本中证实了 Jag1 依赖性肝和免疫缺陷相互作用，从而决定了 ALGS 中的纤维化过程。
