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

Evangelos Triantafyllou; Oltin T Pop; Lucia A Possamai; Annika Wilhelm; Evaggelia Liaskou; Arjuna Singanayagam; Christine Bernsmeier; Wafa Khamri; Gemma Petts; Rebecca Dargue; Scott P Davies; Joseph Tickle; Muhammed Yuksel; Vishal C Patel; Robin D Abeles; Zania Stamataki; Stuart M Curbishley; Yun Ma; Ian D Wilson; Muireann Coen; Kevin J Woollard; Alberto Quaglia; Julia Wendon; Mark R Thursz; David H Adams; Chris J Weston; Charalambos G Antoniades

doi:10.1136/gutjnl-2016-313615

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

Evangelos Triantafyllou, Oltin T Pop, Lucia A Possamai, Annika Wilhelm, Evaggelia Liaskou, Arjuna Singanayagam, Christine Bernsmeier, Wafa Khamri, Gemma Petts, Rebecca Dargue, Scott P Davies, Joseph Tickle, Muhammed Yuksel, Vishal C Patel, Robin D Abeles, Zania Stamataki, Stuart M Curbishley, Yun Ma, Ian D Wilson, Muireann CoenKevin J Woollard, Alberto Quaglia, Julia Wendon, Mark R Thursz, David H Adams, Chris J Weston, Charalambos G Antoniades

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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.

Original language	English
Pages (from-to)	333-347
Number of pages	15
Journal	Gut
Volume	67
Issue number	2
Early online date	8 Jan 2018
DOIs	https://doi.org/10.1136/gutjnl-2016-313615
Publication status	Published - Feb 2018

Keywords

Journal Article

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10.1136/gutjnl-2016-313615Licence: CC BY

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Triantafyllou, E., Pop, O. T., Possamai, L. A., Wilhelm, A., Liaskou, E., Singanayagam, A., Bernsmeier, C., Khamri, W., Petts, G., Dargue, R., Davies, S. P., Tickle, J., Yuksel, M., Patel, V. C., Abeles, R. D., Stamataki, Z., Curbishley, S. M., Ma, Y., Wilson, I. D., ... Antoniades, C. G. (2018). MerTK expressing hepatic macrophages promote the resolution of inflammation in acute liver failure. Gut, 67(2), 333-347. https://doi.org/10.1136/gutjnl-2016-313615

@article{1f265a4272dd4251aeed834f5368e134,

title = "MerTK expressing hepatic macrophages promote the resolution of inflammation in acute liver failure",

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.",

keywords = "Journal Article",

author = "Evangelos Triantafyllou and Pop, {Oltin T} and Possamai, {Lucia A} and Annika Wilhelm and Evaggelia Liaskou and Arjuna Singanayagam and Christine Bernsmeier and Wafa Khamri and Gemma Petts and Rebecca Dargue and Davies, {Scott P} and Joseph Tickle and Muhammed Yuksel and Patel, {Vishal C} and Abeles, {Robin D} and Zania Stamataki and Curbishley, {Stuart M} and Yun Ma and Wilson, {Ian D} and Muireann Coen and Woollard, {Kevin J} and Alberto Quaglia and Julia Wendon and Thursz, {Mark R} and Adams, {David H} and Weston, {Chris J} and Antoniades, {Charalambos G}",

note = "Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.",

year = "2018",

month = feb,

doi = "10.1136/gutjnl-2016-313615",

language = "English",

volume = "67",

pages = "333--347",

journal = "Gut",

issn = "0017-5749",

publisher = "BMJ Publishing Group",

number = "2",

}

Triantafyllou, E, Pop, OT, Possamai, LA, Wilhelm, A, Liaskou, E, Singanayagam, A, Bernsmeier, C, Khamri, W, Petts, G, Dargue, R, Davies, SP, Tickle, J, Yuksel, M , Patel, VC , Abeles, RD, Stamataki, Z, Curbishley, SM, Ma, Y, Wilson, ID, Coen, M, Woollard, KJ, Quaglia, A, Wendon, J, Thursz, MR, Adams, DH, Weston, CJ & Antoniades, CG 2018, 'MerTK expressing hepatic macrophages promote the resolution of inflammation in acute liver failure', Gut, vol. 67, no. 2, pp. 333-347. https://doi.org/10.1136/gutjnl-2016-313615

TY - JOUR

T1 - MerTK expressing hepatic macrophages promote the resolution of inflammation in acute liver failure

AU - Triantafyllou, Evangelos

AU - Pop, Oltin T

AU - Possamai, Lucia A

AU - Wilhelm, Annika

AU - Liaskou, Evaggelia

AU - Singanayagam, Arjuna

AU - Bernsmeier, Christine

AU - Khamri, Wafa

AU - Petts, Gemma

AU - Dargue, Rebecca

AU - Davies, Scott P

AU - Tickle, Joseph

AU - Yuksel, Muhammed

AU - Patel, Vishal C

AU - Abeles, Robin D

AU - Stamataki, Zania

AU - Curbishley, Stuart M

AU - Ma, Yun

AU - Wilson, Ian D

AU - Coen, Muireann

AU - Woollard, Kevin J

AU - Quaglia, Alberto

AU - Wendon, Julia

AU - Thursz, Mark R

AU - Adams, David H

AU - Weston, Chris J

AU - Antoniades, Charalambos G

N1 - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

PY - 2018/2

Y1 - 2018/2

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1136/gutjnl-2016-313615

DO - 10.1136/gutjnl-2016-313615

M3 - Article

C2 - 28450389

SN - 0017-5749

VL - 67

SP - 333

EP - 347

JO - Gut

JF - Gut

IS - 2

ER -

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

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