PD-1 blockade improves Kupffer cell bacterial clearance in acute liver injury
Evangelos Triantafyllou, … , Charalambos G. Antoniades, Mark R. Thursz
Evangelos Triantafyllou, … , Charalambos G. Antoniades, Mark R. Thursz
Published December 15, 2020
Citation Information: J Clin Invest. 2021;131(4):e140196. https://doi.org/10.1172/JCI140196.
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Research Article Hepatology Immunology

PD-1 blockade improves Kupffer cell bacterial clearance in acute liver injury

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.

Authors

Evangelos Triantafyllou, Cathrin L.C. Gudd, Marie-Anne Mawhin, Hannah C. Husbyn, Francesca M. Trovato, Matthew K. Siggins, Thomas O’Connor, Hiromi Kudo, Sujit K. Mukherjee, Julia A. Wendon, Christine Bernsmeier, Robert D. Goldin, Marina Botto, Wafa Khamri, Mark J.W. McPhail, Lucia A. Possamai, Kevin J. Woollard, Charalambos G. Antoniades, Mark R. Thursz

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Figure 2

PD-1 and PD-L1 expression in KCs is increased during the resolution of acute liver injury.

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PD-1 and PD-L1 expression in KCs is increased during the resolution of a...
Hepatic nonparenchymal cells were isolated from livers of baseline (control) and APAP-treated (24 h, 48 h, or 72 h) WT mice. Phenotypic characterization of liver CD45+ leukocytes was done by flow cytometry. (A) Representative flow cytometric gating strategy used to identify MoMFs and liver-resident KCs. (B) Number of MoMFs (red), KCs (blue), and total macrophages (gray) (n = 10–12 per group). (C) Number of PD-1+ MoMFs (red), PD-1+ KCs (blue), and PD-1+ total liver macrophages (gray) (n = 7 per group). (D) Representative histograms and data showing PD-1 expression (MFI) by MoMFs and KCs (n = 7 per group). (E) Number of PD-L1+ MoMFs (red), PD-L1+ KCs (blue), and PD-L1+ total liver macrophages (gray) (n = 7 per group). (F) Representative histograms and data showing PD-L1 expression (MFI) of MoMFs and KCs (n = 7 per group). Results are from 3 (B) and 2 (C–F) independent experiments. Each symbol represents an individual mouse. Data are presented as the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 1-way ANOVA (compared with control). FMO, fluorescence minus one.