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 journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)349-360
Number of pages12
JournalJournal of Hepatology
Volume73
Issue number2
Early online date11 Mar 2020
DOIs
Publication statusE-pub ahead of print - 11 Mar 2020

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