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

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.

Citation

Evangelos Triantafyllou, Cathrin Lc 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 Jw McPhail, Lucia A Possamai, Kevin J Woollard, Charalambos G Antoniades, Mark R Thursz. PD-1 blockade improves Kupffer cell bacterial clearance in acute liver injury. The Journal of clinical investigation. 2021 Feb 15;131(4)

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PMID: 33320839

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