Programmed Death Ligand 1 Is Overexpressed in Liver Macrophages in Chronic Liver Diseases, and Its Blockade Improves the Antibacterial Activity Against Infections

Hepatology. 2021 Jul;74(1):296-311. doi: 10.1002/hep.31644. Epub 2021 Jun 2.

Abstract

Background and aims: Bacterial infections are common and severe in cirrhosis, but their pathogenesis is poorly understood. Dysfunction of liver macrophages may play a role, but information about their function in cirrhosis is limited. Our aims were to investigate the specific profile and function of liver macrophages in cirrhosis and their contribution to infections. Macrophages from human cirrhotic livers were characterized phenotypically by transcriptome analysis and flow cytometry; function was assessed in vivo by single photon emission computerized tomography 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 disk intravital microscopy in a mouse model of chronic liver injury.

Approach and results: Liver macrophages from patients with cirrhosis overexpressed proteins related to immune exhaustion, such as programmed death ligand 1 (PD-L1), macrophage receptor with collagenous structure (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-PD-L1 antibody caused a shift in macrophage phenotype toward 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 programmed cell death receptor 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.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Aged
  • Animals
  • Antigens, CD / metabolism
  • Antigens, Differentiation, Myelomonocytic / metabolism
  • B7-H1 Antigen / antagonists & inhibitors
  • B7-H1 Antigen / metabolism*
  • Bacterial Infections / immunology*
  • Bacterial Infections / prevention & control
  • Biopsy
  • Cells, Cultured
  • Disease Models, Animal
  • Female
  • Gene Expression Profiling
  • Humans
  • Immune Checkpoint Inhibitors / administration & dosage*
  • Liver / immunology
  • Liver / pathology
  • Liver Cirrhosis / complications
  • Liver Cirrhosis / diagnosis
  • Liver Cirrhosis / immunology*
  • Liver Cirrhosis / pathology
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Male
  • Mice
  • Middle Aged
  • Phagocytosis
  • Primary Cell Culture
  • Receptors, Cell Surface / metabolism
  • Receptors, Immunologic / metabolism
  • Severity of Illness Index

Substances

  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • B7-H1 Antigen
  • CD163 antigen
  • CD274 protein, human
  • Immune Checkpoint Inhibitors
  • MARCO protein, human
  • Receptors, Cell Surface
  • Receptors, Immunologic