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. 作者: StephenW 时间: 2020-12-7 09:46