PD-1 blockade improves Kupffer cell bacterial clearance in acute liver injury
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
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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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 8

Monocyte PD-1 expression is increased in patients with ALF.

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Monocyte PD-1 expression is increased in patients with ALF. Phenotypic c...
Phenotypic characterization of monocytes was performed by flow cytometry in PBMCs from HCs (n = 16) and patients with CLD (n = 8) or ALF (n = 20). (A) Representative flow cytometric gating strategy used to identify monocytes and determine their PD-1 expression. Histograms show PD-1 expression in HCs and in patients with CLD or ALF. (B and C) PD-1 expression levels in (B) total monocytes and (C) monocyte subsets (classical, intermediate, and nonclassical). Statistical significance was determined by Mann-Whitney U test. (D) Matrix of correlation of monocyte PD-1 expression (MFI) with clinical scores and biochemical parameters for patients with ALF. INR, international normalized ratio; AST, aspartate aminotransferase; MELD, model for end-stage liver disease; WBC, white blood cell count. (E) PBMCs from HCs and patients with ALF were cultured in the presence of 10% autologous plasma and treated with anti–PD-1 mAb (10 μg/mL) or an isotype-matched control (iso ctrl) (10 μg/mL) prior to E. coli pHrodo phagocytosis assay. Flow cytometric plots and analysis show E. coli pHrodo phagocytosis levels (MFI) in HCs and patients with ALF (n = 9 per group). Results are from 3 independent experiments. Data are presented as the median with the IQR. *P < 0.05, **P < 0.01, ***P < 0.001, and **** P < 0.0001, by Wilcoxon paired test (ALF group) and Mann-Whitney U test (HCs versus patients with ALF).