Alternatively activated macrophages promotes necrosis resolution following acute liver injury

Philip Starkey Lewis; Lara Campana; Niya Aleksieva; Jennifer Ann Cartwright; Alison Mackinnon; Eoghan O'Duibhir; Tim Kendall; Matthieu Vermeren; Adrian Thomson; Victoria Gadd; Benjamin Dwyer; Rhona Aird; Tak-Yung Man; Adriano Giorgio Rossi; Lesley Forrester; B. Kevin Park; Stuart John Forbes

doi:10.1016/j.jhep.2020.02.031

Alternatively activated macrophages promotes necrosis resolution following acute liver injury

Philip Starkey Lewis, Lara Campana, Niya Aleksieva, Jennifer Ann Cartwright, Alison Mackinnon, Eoghan O'Duibhir, Tim Kendall, Matthieu Vermeren, Adrian Thomson, Victoria Gadd, Benjamin Dwyer, Rhona Aird, Tak-Yung Man, Adriano Giorgio Rossi, Lesley Forrester, B. Kevin Park, Stuart John Forbes

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

Background & Aim: Acute liver injury (ALI) can occur if a significant acetaminophen (APAP) overdose presents too late for n-acetylcysteine treatment, which risks deterioration into acute liver failure, systemic inflammation, and death. Macrophages influence the progression and resolution of ALI due to their innate immunological function and paracrine activity. Syngeneic primary bone marrow derived macrophages (BMDMs) were tested as a cell-based therapy in a mouse model of APAP-ALI.
Methods: Several phenotypically-distinct BMDM populations were delivered intravenously to APAP-ALI mice when hepatic necrosis was established, and then evaluated based on their effects on injury, inflammation, immunity, and regeneration. In vivo phagocytosis assayswere used to interrogate the phenotype and function of alternatively-activated BMDMs (AAMs) post-injection. Finally, primary human AAMs sourced from healthy volunteers were evaluated in immunocompetent APAP-ALI mice.
Results:BMDMs rapidly localised in liver and spleen within four hours of administration. Injection of AAMs specifically reduced hepatocellular necrosis, HMGB1 translocation, and infiltrating neutrophils following APAP-ALI. AAM delivery also stimulated proliferation in hepatocytes and endothelium, and reduced levels of several circulating proinflammatory cytokines within 24 hours. AAMs displayed a high phagocytic activity both in vitro and in injured liver tissue post-injection. Crosstalk with the host innate immune system was evidenced by reduced infiltrating host Ly6Chi macrophages in AAM-treated mice. Importantly, therapeutic efficacy was partially recapitulated using clinical-grade primary human AAMs in immunocompetent APAP-ALI mice underscoring translational potential.
Conclusion: We identify that AAMs have value as a cell-based therapy in an experimental model of APAP-ALI. Human AAMs warrant further evaluation as a potential cell-based therapy for APAP overdose patients with established liver injury.

Original language	English
Pages (from-to)	349-360
Number of pages	12
Journal	Journal of Hepatology
Volume	73
Issue number	2
Early online date	11 Mar 2020
DOIs	https://doi.org/10.1016/j.jhep.2020.02.031
Publication status	E-pub ahead of print - 11 Mar 2020

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10.1016/j.jhep.2020.02.031

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https://www.sciencedirect.com/science/article/pii/S0168827820301331

Collaboration with Syncona to enhance the MATCH trial
Forbes, S. & Campbell, J.
UK industry, commerce and public corporations
23/01/18 → 31/12/22
Project: Research
Evaluation of human macrophages as a cell therapy for acute liver injury
Forbes, S. & Starkey Lewis, P.
MRC
1/07/17 → 30/06/18
Project: Research
Tissue Repair PhD Programme
Forbes, S. & Becker, C.
UK-based charities
12/09/16 → 12/03/21
Project: Research

CRM Imaging Facility
Matthieu Vermeren (Manager)
Centre for Regenerative Medicine
Facility/equipment: Facility
Edinburgh Preclinical Imaging
Carmel Moran (Manager), Adrian Thomson (Manager), Ross J Lennen (Manager), Adriana Tavares (Manager), Carlos J. Alcaide-Corral (Manager), Tim Morgan (Other), Islay Cranston (Other) & Kerry O'Rourke (Other)
Deanery of Clinical Sciences
Facility/equipment: Facility
Institute for Regeneration and Repair Flow Cytometry Facility
Shonna Johnston (Manager), Fiona Rossi (Manager), Claire Cryer (Other) & Ailsa Laird (Other)
Institute of Regeneration and Repair
Facility/equipment: Facility

Timothy Kendall
- Tim.Kendalled.acuk
- Deanery of Clinical Sciences - Personal Chair of Liver Pathology
- Centre for Inflammation Research
- Edinburgh Pathology
Person: Academic: Research Active

Cite this

Starkey Lewis, P., Campana, L., Aleksieva, N., Cartwright, J. A., Mackinnon, A., O'Duibhir, E., Kendall, T., Vermeren, M., Thomson, A., Gadd, V., Dwyer, B., Aird, R., Man, T.-Y., Rossi, A. G., Forrester, L., Park, B. K., & Forbes, S. J. (2020). Alternatively activated macrophages promotes necrosis resolution following acute liver injury. Journal of Hepatology, 73(2), 349-360. Advance online publication. https://doi.org/10.1016/j.jhep.2020.02.031

@article{04cd9502b7444b3a9eb01674f5043782,

title = "Alternatively activated macrophages promotes necrosis resolution following acute liver injury",

abstract = "Background & Aim: Acute liver injury (ALI) can occur if a significant acetaminophen (APAP) overdose presents too late for n-acetylcysteine treatment, which risks deterioration into acute liver failure, systemic inflammation, and death. Macrophages influence the progression and resolution of ALI due to their innate immunological function and paracrine activity. Syngeneic primary bone marrow derived macrophages (BMDMs) were tested as a cell-based therapy in a mouse model of APAP-ALI. Methods: Several phenotypically-distinct BMDM populations were delivered intravenously to APAP-ALI mice when hepatic necrosis was established, and then evaluated based on their effects on injury, inflammation, immunity, and regeneration. In vivo phagocytosis assayswere used to interrogate the phenotype and function of alternatively-activated BMDMs (AAMs) post-injection. Finally, primary human AAMs sourced from healthy volunteers were evaluated in immunocompetent APAP-ALI mice. Results:BMDMs rapidly localised in liver and spleen within four hours of administration. Injection of AAMs specifically reduced hepatocellular necrosis, HMGB1 translocation, and infiltrating neutrophils following APAP-ALI. AAM delivery also stimulated proliferation in hepatocytes and endothelium, and reduced levels of several circulating proinflammatory cytokines within 24 hours. AAMs displayed a high phagocytic activity both in vitro and in injured liver tissue post-injection. Crosstalk with the host innate immune system was evidenced by reduced infiltrating host Ly6Chi macrophages in AAM-treated mice. Importantly, therapeutic efficacy was partially recapitulated using clinical-grade primary human AAMs in immunocompetent APAP-ALI mice underscoring translational potential.Conclusion: We identify that AAMs have value as a cell-based therapy in an experimental model of APAP-ALI. Human AAMs warrant further evaluation as a potential cell-based therapy for APAP overdose patients with established liver injury.",

author = "{Starkey Lewis}, Philip and Lara Campana and Niya Aleksieva and Cartwright, {Jennifer Ann} and Alison Mackinnon and Eoghan O'Duibhir and Tim Kendall and Matthieu Vermeren and Adrian Thomson and Victoria Gadd and Benjamin Dwyer and Rhona Aird and Tak-Yung Man and Rossi, {Adriano Giorgio} and Lesley Forrester and Park, {B. Kevin} and Forbes, {Stuart John}",

year = "2020",

month = mar,

day = "11",

doi = "10.1016/j.jhep.2020.02.031",

language = "English",

volume = "73",

pages = "349--360",

journal = "Journal of Hepatology",

issn = "0168-8278",

publisher = "Elsevier",

number = "2",

}

Starkey Lewis, P, Campana, L, Aleksieva, N, Cartwright, JA, Mackinnon, A, O'Duibhir, E, Kendall, T, Vermeren, M, Thomson, A, Gadd, V, Dwyer, B, Aird, R, Man, T-Y, Rossi, AG , Forrester, L, Park, BK & Forbes, SJ 2020, 'Alternatively activated macrophages promotes necrosis resolution following acute liver injury', Journal of Hepatology, vol. 73, no. 2, pp. 349-360. https://doi.org/10.1016/j.jhep.2020.02.031

TY - JOUR

T1 - Alternatively activated macrophages promotes necrosis resolution following acute liver injury

AU - Starkey Lewis, Philip

AU - Campana, Lara

AU - Aleksieva, Niya

AU - Cartwright, Jennifer Ann

AU - Mackinnon, Alison

AU - O'Duibhir, Eoghan

AU - Kendall, Tim

AU - Vermeren, Matthieu

AU - Thomson, Adrian

AU - Gadd, Victoria

AU - Dwyer, Benjamin

AU - Aird, Rhona

AU - Man, Tak-Yung

AU - Rossi, Adriano Giorgio

AU - Forrester, Lesley

AU - Park, B. Kevin

AU - Forbes, Stuart John

PY - 2020/3/11

Y1 - 2020/3/11

N2 - Background & Aim: Acute liver injury (ALI) can occur if a significant acetaminophen (APAP) overdose presents too late for n-acetylcysteine treatment, which risks deterioration into acute liver failure, systemic inflammation, and death. Macrophages influence the progression and resolution of ALI due to their innate immunological function and paracrine activity. Syngeneic primary bone marrow derived macrophages (BMDMs) were tested as a cell-based therapy in a mouse model of APAP-ALI. Methods: Several phenotypically-distinct BMDM populations were delivered intravenously to APAP-ALI mice when hepatic necrosis was established, and then evaluated based on their effects on injury, inflammation, immunity, and regeneration. In vivo phagocytosis assayswere used to interrogate the phenotype and function of alternatively-activated BMDMs (AAMs) post-injection. Finally, primary human AAMs sourced from healthy volunteers were evaluated in immunocompetent APAP-ALI mice. Results:BMDMs rapidly localised in liver and spleen within four hours of administration. Injection of AAMs specifically reduced hepatocellular necrosis, HMGB1 translocation, and infiltrating neutrophils following APAP-ALI. AAM delivery also stimulated proliferation in hepatocytes and endothelium, and reduced levels of several circulating proinflammatory cytokines within 24 hours. AAMs displayed a high phagocytic activity both in vitro and in injured liver tissue post-injection. Crosstalk with the host innate immune system was evidenced by reduced infiltrating host Ly6Chi macrophages in AAM-treated mice. Importantly, therapeutic efficacy was partially recapitulated using clinical-grade primary human AAMs in immunocompetent APAP-ALI mice underscoring translational potential.Conclusion: We identify that AAMs have value as a cell-based therapy in an experimental model of APAP-ALI. Human AAMs warrant further evaluation as a potential cell-based therapy for APAP overdose patients with established liver injury.

AB - Background & Aim: Acute liver injury (ALI) can occur if a significant acetaminophen (APAP) overdose presents too late for n-acetylcysteine treatment, which risks deterioration into acute liver failure, systemic inflammation, and death. Macrophages influence the progression and resolution of ALI due to their innate immunological function and paracrine activity. Syngeneic primary bone marrow derived macrophages (BMDMs) were tested as a cell-based therapy in a mouse model of APAP-ALI. Methods: Several phenotypically-distinct BMDM populations were delivered intravenously to APAP-ALI mice when hepatic necrosis was established, and then evaluated based on their effects on injury, inflammation, immunity, and regeneration. In vivo phagocytosis assayswere used to interrogate the phenotype and function of alternatively-activated BMDMs (AAMs) post-injection. Finally, primary human AAMs sourced from healthy volunteers were evaluated in immunocompetent APAP-ALI mice. Results:BMDMs rapidly localised in liver and spleen within four hours of administration. Injection of AAMs specifically reduced hepatocellular necrosis, HMGB1 translocation, and infiltrating neutrophils following APAP-ALI. AAM delivery also stimulated proliferation in hepatocytes and endothelium, and reduced levels of several circulating proinflammatory cytokines within 24 hours. AAMs displayed a high phagocytic activity both in vitro and in injured liver tissue post-injection. Crosstalk with the host innate immune system was evidenced by reduced infiltrating host Ly6Chi macrophages in AAM-treated mice. Importantly, therapeutic efficacy was partially recapitulated using clinical-grade primary human AAMs in immunocompetent APAP-ALI mice underscoring translational potential.Conclusion: We identify that AAMs have value as a cell-based therapy in an experimental model of APAP-ALI. Human AAMs warrant further evaluation as a potential cell-based therapy for APAP overdose patients with established liver injury.

U2 - 10.1016/j.jhep.2020.02.031

DO - 10.1016/j.jhep.2020.02.031

M3 - Article

SN - 0168-8278

VL - 73

SP - 349

EP - 360

JO - Journal of Hepatology

JF - Journal of Hepatology

IS - 2

ER -

Alternatively activated macrophages promotes necrosis resolution following acute liver injury

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Projects

Collaboration with Syncona to enhance the MATCH trial

Evaluation of human macrophages as a cell therapy for acute liver injury

Tissue Repair PhD Programme

Equipment

CRM Imaging Facility

Edinburgh Preclinical Imaging

Institute for Regeneration and Repair Flow Cytometry Facility

Profiles

Timothy Kendall

Cite this