Abstract
Patients with acute liver failure (ALF) have systemic innate immune suppression and increased susceptibility to infections. Programmed cell death 1 (PD-1) expression by macrophages has been associated with immune suppression during sepsis and cancer. We therefore examined the role of the programmed cell death 1/programmed death ligand 1 (PD-1/PD-L1) pathway in regulating Kupffer cell (KC) inflammatory and antimicrobial responses in acetaminophen-induced (APAP-induced) acute liver injury. Using intravital imaging and flow cytometry, we found impaired KC bacterial clearance and systemic bacterial dissemination in mice with liver injury. We detected increased PD-1 and PD-L1 expression in KCs and lymphocyte subsets, respectively, during injury resolution. Gene expression profiling of PD-1+ KCs revealed an immune-suppressive profile and reduced pathogen responses. Compared with WT mice, PD-1–deficient mice and anti–PD-1–treated mice with liver injury showed improved KC bacterial clearance, a reduced tissue bacterial load, and protection from sepsis. Blood samples from patients with ALF revealed enhanced PD-1 and PD-L1 expression by monocytes and lymphocytes, respectively, and that soluble PD-L1 plasma levels could predict outcomes and sepsis. PD-1 in vitro blockade restored monocyte functionality. Our study describes a role for the PD-1/PD-L1 axis in suppressing KC and monocyte antimicrobial responses after liver injury and identifies anti–PD-1 immunotherapy as a strategy to reduce infection susceptibility in ALF.
Highlights
Acute liver failure (ALF) is a rare clinical syndrome in which coagulopathy, jaundice, and hepatic encephalopathy arise in the context of acute hepatic injury without preexisting chronic liver disease (CLD) [1, 2]
We further examined bacteria internalization by Kupffer cell (KC) using intravital imaging in mice challenged with pHrodo E. coli, a pH-sensitive assay indicating phagolysosome acidification, which confirmed a reduced KC bacterial uptake capacity in APAP-treated mice (Supplemental Figure 1, B and C)
KCs from APAP-treated mice were characterized by a decrease in bacterial killing ability, as indicated by the greater number of viable E. coli recovered from KCs (Figure 1E and Supplemental Figure 1E)
Summary
Acute liver failure (ALF) is a rare clinical syndrome in which coagulopathy, jaundice, and hepatic encephalopathy arise in the context of acute hepatic injury without preexisting chronic liver disease (CLD) [1, 2]. The initiating event in ALF is overwhelming hepatocyte death, mortality occurs as a result of profound activation of hepatic and systemic inflammatory responses and the associated complications of multiorgan failure, immune paresis, and sepsis [3]. Bacterial infections are common complications of ALF, occurring late (>5 days after hospital admission) in 35%–40% of patients and are considered a leading cause of mortality [3,4,5]. This is a consequence of ALF-related immune paresis and the invasive nature of critical care support that predisposes patients to nosocomial infections [3]. Monocytes of patients with ALF are hyporesponsive to microbial challenge and show reduced proinflammatory cytokine secretion, impaired Escherichia coli bacterial uptake, and an M2-like phenotype that favors the resolution of inflammation [4,5,6, 8]
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