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

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.

Macrophages in Chronic Liver Failure: Diversity, Plasticity and Therapeutic Targeting

“…We also found up-regulated PD-1 and PD-L1 expression of peripheral monocytes and lymphocytes in patients with ALF and increased plasma soluble PD-L1 levels predicting mortality and development of sepsis (227). Similarly, another study demonstrated overexpression of PD-L1 in peripheral monocytes and liver macrophages in cirrhotic patients who displayed impaired hepatic bacterial uptake (228). Interestingly, monocyte PD-L1 was associated with disease severity and infection risk in cirrhosis while anti-PD-L1 mAb treatment restored the phagocytic capacity of macrophages and reduced bacterial dissemination in mice with chronic liver injury (228).…”

“…Similarly, another study demonstrated overexpression of PD-L1 in peripheral monocytes and liver macrophages in cirrhotic patients who displayed impaired hepatic bacterial uptake (228). Interestingly, monocyte PD-L1 was associated with disease severity and infection risk in cirrhosis while anti-PD-L1 mAb treatment restored the phagocytic capacity of macrophages and reduced bacterial dissemination in mice with chronic liver injury (228). These studies indicate that immune checkpoint blockade may be an effective and safe strategy for restoration of defective antibacterial responses in chronic liver failure patients, where conventional treatment options are currently very limited.…”

COVID-19 and liver disease: mechanistic and clinical perspectives

“…This immune dysfunction includes reduced components of the complement system, macrophage activation, impaired lymphocyte and neutrophil function, Tolllike receptor upregulation, and intestinal dysbiosis 9,79 . Although research attention has mostly focused on mechanisms leading to severe bacterial infection 80 , CAID has also been shown to predispose to a variety of viral or fungal-related disease 81 . Whether patients with CLD and cirrhosis are more susceptible to SARS-CoV-2 infection has been the focus of much attention throughout 2020.…”

The Hepatic Sinusoid in Chronic Liver Disease: The Optimal Milieu for Cancer

“…On the other hand, the persistent activation of hepatic macrophages may result in immune exhaustion, a scenario with inefficient and immunosuppressive macrophages which are unable to phagocyte pathogens, and which are associated with an increased risk of infections in patients [123]. Indeed, the blocking of PD-L1 (a marker of macrophage exhaustion) improved macrophage function in an animal model of chronic liver injury [123], suggesting that achieving an anti-inflammatory but also functional macrophage phenotype is of importance for CLD, and should be a matter of future study. For this reason, and considering their interactions with the other sinusoidal cells during liver injury, KCs are being studied as therapeutic targets for different liver diseases [107,108].…”

“…In this regard, during CLD, the sinusoidal microenvironment rich in proinflammatory cytokines and ROS, alone or in combination with the source of liver injury (e.g., alcohol, a virus, excessive lipids) may induce increased DNA damage and promote de novo carcinogenesis [256,257]. Furthermore, the suppressed state of the immune system during CLD may contribute to the altered removal of dysfunctional cells [123,[258][259][260], further enhancing tumour initiation.…”