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

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...

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Published in:Hepatology (Baltimore, Md.) Md.), 2021-07, Vol.74 (1), p.296-311
Main Authors: Pose, Elisa, Coll, Mar, Martínez‐Sánchez, Celia, Zeng, Zhutian, Surewaard, Bas G. J., Català, Cristina, Velasco‐de Andrés, María, Lozano, Juan José, Ariño, Sílvia, Fuster, David, Niñerola‐Bazán, Aida, Graupera, Isabel, Muñoz, Érica, Lozano, Francisco, Sancho‐Bru, Pau, Kubes, Paul, Ginès, Pere
Format: Article
Language:English
Subjects:
Aged
Animals
Antibacterial activity
Antigens, CD - metabolism
Antigens, Differentiation, Myelomonocytic - metabolism
Antimicrobial activity
Apoptosis
B7-H1 Antigen - antagonists & inhibitors
B7-H1 Antigen - metabolism
Bacterial infections
Bacterial Infections - immunology
Bacterial Infections - prevention & control
Biopsy
CD163 antigen
Cell death
Cells, Cultured
Cirrhosis
Collagen
Computed tomography
Disease Models, Animal
Enzyme-linked immunosorbent assay
Female
Flow cytometry
Gene Expression Profiling
Hepatology
Humans
Immune Checkpoint Inhibitors - administration & dosage
Infections
Ligands
Liver
Liver - immunology
Liver - pathology
Liver cirrhosis
Liver Cirrhosis - complications
Liver Cirrhosis - diagnosis
Liver Cirrhosis - immunology
Liver Cirrhosis - pathology
Liver diseases
Macrophages
Macrophages - immunology
Macrophages - metabolism
Male
MARCO protein
Mice
Middle Aged
Monocytes
Original
PD-L1 protein
Phagocytes
Phagocytosis
Phenotypes
Primary Cell Culture
Receptors, Cell Surface - metabolism
Receptors, Immunologic - metabolism
Serum levels
Severity of Illness Index
Transcriptomes
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Summary: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.
ISSN:0270-9139
1527-3350
DOI:10.1002/hep.31644