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

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140196.1-20201214082252-covered-253bed37ca4c1ab43d105aefdf7b5536.pdfPublished version12.67 MBAdobe PDFView/Open
Title: PD-1 blockade improves Kupffer cell bacterial clearance in acute liver injury
Authors: Triantafyllou, E
Gudd, C
Mawhin, M-A
Husbyn, H
Trovato, F
Siggins, M
O'Connor, T
Kudo, H
Mukherjee, SK
Wendon, JA
Bernsmeier, C
Goldin, R
Botto, M
Khamri, W
McPhail, M
Possamai, L
Woollard, K
Charalambos, AG
Thursz, M
Item Type: Journal Article
Abstract: Acute liver failure (ALF) patients display systemic innate immune suppression and increased susceptibility to infections. PD-1 expression by macrophages has been associated with immune suppression during sepsis and cancer. We therefore examined the role of PD-1/PD-L1 pathway in regulating Kupffer cell inflammatory and antimicrobial responses in acetaminophen (APAP) induced acute liver injury. Using intravital imaging and flow cytometry we found impaired Kupffer cell bacterial clearance and systemic bacterial dissemination in mice with liver injury. Increased PD-1 and PD-L1 expression was detected in Kupffer cells and lymphocyte subsets, respectively, during resolution of injury. Gene expression profiling of PD-1+ Kupffer cells revealed an immune-suppressive profile and reduced pathogen responses. Compared to wild-type, PD-1 deficient or anti-PD-1 treated mice with liver injury showed improved Kupffer cell bacterial clearance, reduced tissue bacterial load and protection from sepsis. Blood sample analyses of ALF patients revealed enhanced PD-1 and PD-L1 expression of monocytes and lymphocytes, respectively, and that plasma soluble PD-L1 levels predict patient outcome and sepsis. PD-1 in vitro blockade restored monocyte functionality. Our study describes a role for PD-1/PD-L1 axis in suppressing Kupffer cell and monocyte antimicrobial responses after liver injury and suggests anti-PD-1 immunotherapy as a strategy to reduce infection susceptibility in ALF.
Issue Date: 15-Dec-2020
Date of Acceptance: 10-Dec-2020
URI: http://hdl.handle.net/10044/1/84973
DOI: 10.1172/JCI140196
ISSN: 0021-9738
Publisher: American Society for Clinical Investigation
Start Page: 1
End Page: 16
Journal / Book Title: Journal of Clinical Investigation
Volume: 131
Issue: 4
Copyright Statement: Copyright © 2020 American Society for Clinical Investigation
Sponsor/Funder: Medical Research Council (MRC)
Funder's Grant Number: MR/R014019/1
Keywords: Hepatology
Immunology
Innate immunity
Macrophages
Immunology
11 Medical and Health Sciences
Publication Status: Published
Online Publication Date: 2020-12-15
Appears in Collections:Department of Immunology and Inflammation
Department of Metabolism, Digestion and Reproduction
National Heart and Lung Institute
Faculty of Medicine