PD-L1在慢性肝病中的肝巨噬细胞中过表达，其阻断作用可提高

StephenW

PD‐L1 is overexpressed in liver macrophages in chronic liver diseases and its blockade improves the antibacterial activity against infections
Elisa Pose
Mar Coll
Celia Martínez‐Sánchez
Zhutian Zeng
Bas G.J. Surewaard
Cristina Català
María Velasco
Juanjo Lozano
Sílvia Ariño
David Fuster
Aida Niñerola‐Bazán
… See all authors
First published: 20 November 2020
https://doi.org/10.1002/hep.31644

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi:10.1002/hep.31644
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Abstract
Objective

Bacterial infections are common and severe in cirrhosis, but its pathogenesis is poorly understood. Dysfunction of liver macrophages may play a role, but information about their function in cirrhosis is limited. Aims were to investigate the specific profile and function of liver macrophages in cirrhosis and their contribution to infections.
Design

Macrophages from human cirrhotic livers were characterized phenotypically by transcriptome analysis and flow cytometry; function was assessed in vivo by SPECT in patients with cirrhosis. Serum levels of specific proteins and expression in peripheral monocytes were determined by ELISA and flow cytometry. In vivo phagocytic activity of liver macrophages was measured by spinning disc intravital microscopy in a mouse model of chronic liver injury.
Results

Liver macrophages from patients with cirrhosis overexpressed psroteins related to immune exhaustion such as PD‐L1, MARCO and CD163. In vivo phagocytic activity of liver macrophages in patients with cirrhosis was markedly impaired. Monocytes from patients with cirrhosis showed overexpression of PD‐L1 that paralleled disease severity, correlated with its serum levels, and was associated with increased risk of infections. Blockade of PD‐L1 with anti‐PDL1 antibody caused a shift in macrophage phenotype towards a less immunosuppressive profile, restored liver macrophage in vivo phagocytic activity and reduced bacterial dissemination.
Conclusion

Liver cirrhosis is characterized by a remarkable impairment of phagocytic function of macrophages associated with an immunosuppressive transcriptome profile. The PD‐1/PD‐L1 axis plays a major role in the impaired activity of liver macrophages. PD‐L1 blockade reverses the immune suppressive profile and increases antimicrobial activity of liver macrophages in cirrhosis.

StephenW

PD-L1在慢性肝病中的肝巨噬细胞中过表达，其阻断作用可提高对感染的抗菌活性
艾丽莎·珀斯（Elisa Pose）
马尔·科尔
西莉亚·马丁内斯·桑切斯
曾竹田
巴斯·吉苏瓦德
克里斯蒂娜（CristinaCatalà）
玛丽亚·贝拉斯科（MaríaVelasco）
胡安·洛萨诺（Juanjo Lozano）
西尔维亚·阿里尼奥（SílviaAriño）
大卫·弗斯特
艾达（AidaNiñerola-Bazán）
…查看所有作者
首次发布：2020年11月20日
https://doi.org/10.1002/hep.31644

本文已被接受发表，并且经过了完整的同行评审，但尚未经过复制编辑，排版，分页和校对过程，因此可能会导致此版本与“记录版本”之间的差异。请引用本文作为doi：10.1002 / hep.31644
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目的

细菌感染在肝硬化中常见且严重，但对其发病机理了解甚少。肝巨噬细胞功能障碍可能起作用，但有关其在肝硬化中功能的信息有限。目的是研究肝巨噬细胞在肝硬化中的具体特征和功能及其对感染的影响。
设计

通过转录组分析和流式细胞仪对人类肝硬化肝脏的巨噬细胞进行表型鉴定。通过SPECT对肝硬化患者的体内功能进行评估。通过ELISA和流式细胞术确定血清中特定蛋白质的水平和在外周单核细胞中的表达。肝巨噬细胞的体内吞噬活性是通过旋转盘活体显微镜在慢性肝损伤的小鼠模型中测量的。
结果

肝硬化患者的肝巨噬细胞过表达与免疫力衰竭有关的蛋白，例如PD-L1，MARCO和CD163。肝硬化患者肝巨噬细胞的体内吞噬活性明显受损。肝硬化患者的单核细胞显示PD-L1过表达，与疾病严重程度平行，与血清水平相关，并与感染风险增加相关。用抗PDL1抗体阻断PD-L1会导致巨噬细胞表型向免疫抑制特征降低，恢复肝脏巨噬细胞的体内吞噬活性并减少细菌传播。
结论

肝硬化的特征是巨噬细胞吞噬功能显着受损，并伴有免疫抑制转录组特征。 PD-1 / PD-L1轴在肝巨噬细胞活性受损中起主要作用。 PD-L1阻滞剂可逆转免疫抑制特性，并增强肝硬化中肝巨噬细胞的抗菌活性。