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MerTK expressing hepatic macrophages promote the resolution of inflammation in acute liver failure

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Title: MerTK expressing hepatic macrophages promote the resolution of inflammation in acute liver failure
Authors: Triantafyllou, E
Pop, O
Possamai, L
Wilhelm, A
Liaskou, E
Singanayagam, A
Bernsmeier, C
Khamri, W
Petts, G
Dargue, R
Davies, S
Tickle, J
Yuksel, M
Patel, V
Abeles, R
Stamataki, Z
Curbishley, S
Ma, Y
Wilson, I
Coen, M
Woollard, K
Quaglia, A
Wendon, J
Thursz, M
Adams, D
Weston, C
Antoniades, C
Item Type: Journal Article
Abstract: Objective Acute liver failure (ALF) is characterised by overwhelming hepatocyte death and liver inflammation with massive infiltration of myeloid cells in necrotic areas. The mechanisms underlying resolution of acute hepatic inflammation are largely unknown. Here, we aimed to investigate the impact of Mer tyrosine kinase (MerTK) during ALF and also examine how the microenvironmental mediator, secretory leucocyte protease inhibitor (SLPI), governs this response. Design Flow cytometry, immunohistochemistry, confocal imaging and gene expression analyses determined the phenotype, functional/transcriptomic profile and tissue topography of MerTK+ monocytes/macrophages in ALF, healthy and disease controls. The temporal evolution of macrophage MerTK expression and its impact on resolution was examined in APAP-induced acute liver injury using wild-type (WT) and Mer-deficient (Mer−/−) mice. SLPI effects on hepatic myeloid cells were determined in vitro and in vivo using APAP-treated WT mice. Results We demonstrate a significant expansion of resolution-like MerTK+HLA-DRhigh cells in circulatory and tissue compartments of patients with ALF. Compared with WT mice which show an increase of MerTK+MHCIIhigh macrophages during the resolution phase in ALF, APAP-treated Mer−/− mice exhibit persistent liver injury and inflammation, characterised by a decreased proportion of resident Kupffer cells and increased number of neutrophils. Both in vitro and in APAP-treated mice, SLPI reprogrammes myeloid cells towards resolution responses through induction of a MerTK+HLA-DRhigh phenotype which promotes neutrophil apoptosis and their subsequent clearance. Conclusions We identify a hepatoprotective, MerTK+, macrophage phenotype that evolves during the resolution phase following ALF and represents a novel immunotherapeutic target to promote resolution responses following acute liver injury.
Issue Date: 27-Apr-2017
Date of Acceptance: 31-Mar-2017
URI: http://hdl.handle.net/10044/1/46258
DOI: https://dx.doi.org/10.1136/gutjnl-2016-313615
ISSN: 1468-3288
Publisher: BMJ Publishing Group
Start Page: 333
End Page: 347
Journal / Book Title: Gut
Volume: 67
Copyright Statement: © Article author (or their employer) 2017. Produced by BMJ Publishing Group Ltd (& BSG) under licence. This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/
Sponsor/Funder: Medical Research Council (MRC)
Wellcome Trust
Rosetrees Trust
Stoneygate Trust
Funder's Grant Number: MR/K010514/1
107303/Z/15/Z
A1035
n/a
Keywords: ACUTE LIVER FAILURE
IMMUNOLOGY
INFLAMMATION
MACROPHAGES
1103 Clinical Sciences
1114 Paediatrics And Reproductive Medicine
Gastroenterology & Hepatology
Publication Status: Published
Appears in Collections:Department of Medicine (up to 2019)