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 6

PD-1 blockade improves KC bacterial clearance and confers protection from sepsis in mice with acute liver injury.

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PD-1 blockade improves KC bacterial clearance and confers protection fro...
Baseline (control) and APAP-treated (72 h) WT mice, dosed with isotype control (iso) or anti–PD-1 mAb 48 hours after APAP treatment, were intravenously challenged with E. coli. (A) Plasma alanine transaminase (ALT) levels (U/L) and (B) hepatic necrosis scores (n = 4–5 per group). (C) Representative intravital liver images from APAP-treated (72 h) mice (20 min after infection). Macrophages and endothelial cells were stained with fluorescently labeled anti-F4/80 (purple) and anti-CD31 (blue) antibodies, respectively; GFP+ E. coli (green). Scale bars: 50 μm. (D) Intravital liver imaging analysis showing the amount of macrophage-captured E. coli per FOV (n = 3–4 per group). (E) Number of free E. coli in blood measured by flow cytometry (n = 7 per group). (F) Mouse sepsis scores over time following E. coli infection (n = 4–5 per group). (G) CFU analysis showing bacterial burden in the liver, spleen, lungs, and kidneys 24 hours after infection (n = 4–5 per group). Results in A–G are for 2 independent experiments. Each symbol represents an individual mouse. Data are presented as the mean ± SEM. *P < 0.05, **P < 0.01, and ****P < 0.0001, by 1-way ANOVA (A–E and G) or 2-way, repeated-measures ANOVA (F).