First Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
First Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany; Bioinformatics Core Facility, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
J Hepatol. 2022 Dec;77(6):1532-1544. doi: 10.1016/j.jhep.2022.06.025. Epub 2022 Jul 5.
BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is a progressive cholangiopathy characterised by fibrotic stricturing and inflammation of bile ducts, which seems to be driven by a maladaptive immune response to bile duct injury. The histological finding of dendritic cell expansion in portal fields of patients with PSC prompted us to investigate the role of dendritic cells in orchestrating the immune response to bile duct injury.
Dendritic cell numbers and subtypes were determined in different mouse models of cholangitis by flow cytometry based on lineage-imprinted markers. Findings were confirmed by immunofluorescence microscopy of murine livers, and liver samples from patients with PSC were compared to control samples from bariatric surgery patients. Using genetic tools, selected dendritic cell subsets were depleted in murine cholangitis. The dendritic cell response to bile duct injury was determined by single-cell transcriptomics.
Cholangitis mouse models were characterised by selective intrahepatic expansion of type 2 conventional dendritic cells, whereas plasmacytoid and type 1 conventional dendritic cells were not expanded. Expansion of type 2 conventional dendritic cells in human PSC lesions was confirmed by histology. Depletion studies revealed a proinflammatory role of type 2 conventional dendritic cells. Single-cell transcriptomics confirmed inflammatory maturation of the intrahepatic type 2 conventional dendritic cells and identified dendritic cell-derived inflammatory mediators.
Cholangitis is characterised by intrahepatic expansion and inflammatory maturation of type 2 conventional dendritic cells in response to biliary injury. Therefore, type 2 conventional dendritic cells and their inflammatory mediators might be potential therapeutic targets for the treatment of PSC.
Primary sclerosing cholangitis (PSC) is an inflammatory liver disease of the bile ducts for which there is no effective treatment. Herein, we show that the inflammatory immune response to bile duct injury is organised by a specific subtype of immune cell called conventional type 2 dendritic cells. Our findings suggest that this cell subtype and the inflammatory molecules it produces are potential therapeutic targets for PSC.
原发性硬化性胆管炎（PSC）是一种进行性胆管疾病，其特征为胆管纤维化和炎症，似乎是由胆管损伤后的适应性免疫反应驱动的。PSC 患者门脉区树突状细胞扩张的组织学发现促使我们研究树突状细胞在协调胆管损伤免疫反应中的作用。
通过基于谱系印迹标记的流式细胞术确定不同胆管炎小鼠模型中的树突状细胞数量和亚型。通过对小鼠肝脏的免疫荧光显微镜检查和与减肥手术患者对照样本的比较，验证了这些发现。使用遗传工具，在小鼠胆管炎中耗竭了选定的树突状细胞亚群。通过单细胞转录组学确定了树突状细胞对胆管损伤的反应。
胆管炎小鼠模型的特征是 2 型常规树突状细胞在肝内选择性扩增，而浆细胞样和 1 型常规树突状细胞未扩增。组织学证实了人类 PSC 病变中 2 型常规树突状细胞的扩增。耗竭研究表明 2 型常规树突状细胞具有促炎作用。单细胞转录组学证实了肝内 2 型常规树突状细胞的炎症成熟，并鉴定了树突状细胞衍生的炎症介质。
胆管炎的特征是在胆管损伤后，肝内 2 型常规树突状细胞的扩增和炎症成熟。因此，2 型常规树突状细胞及其炎症介质可能是 PSC 治疗的潜在治疗靶点。
原发性硬化性胆管炎（PSC）是一种胆管炎症性疾病，目前尚无有效治疗方法。本文表明，对胆管损伤的炎症免疫反应是由一种称为常规 2 型树突状细胞的特定免疫细胞亚群组织的。我们的研究结果表明，这种细胞亚群及其产生的炎症分子可能是 PSC 的潜在治疗靶点。
