PMID- 32169610 OWN - NLM STAT- MEDLINE DCOM- 20211103 LR - 20211103 IS - 1600-0641 (Electronic) IS - 0168-8278 (Print) IS - 0168-8278 (Linking) VI - 73 IP - 2 DP - 2020 Aug TI - Alternatively activated macrophages promote resolution of necrosis following acute liver injury. PG - 349-360 LID - S0168-8278(20)30133-1 [pii] LID - 10.1016/j.jhep.2020.02.031 [doi] AB - BACKGROUND & AIM: Following acetaminophen (APAP) overdose, acute liver injury (ALI) can occur in patients that present too late for N-acetylcysteine treatment, potentially leading to 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-induced ALI (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 assays were 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 to the liver and spleen within 4 h 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 h. AAMs displayed a high phagocytic activity both in vitro and in injured liver tissue post-injection. Crosstalk with the host innate immune system was demonstrated by reduced infiltrating host Ly6C(hi) macrophages in AAM-treated mice. Importantly, therapeutic efficacy was partially recapitulated using clinical-grade primary human AAMs in immunocompetent APAP-ALI mice, underscoring the translational potential of these findings. 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. LAY SUMMARY: After an overdose of acetaminophen (paracetamol), some patients present to hospital too late for the current antidote (N-acetylcysteine) to be effective. We tested whether macrophages, an injury-responsive leukocyte that can scavenge dead/dying cells, could serve as a cell-based therapy in an experimental model of acetaminophen overdose. Injection of alternatively activated macrophages rapidly reduced liver injury and reduced several mediators of inflammation. Macrophages show promise to serve as a potential cell-based therapy for acute liver injury. CI - Copyright (c) 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. FAU - Starkey Lewis, Philip AU - Starkey Lewis P AD - MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh, United Kingdom; UK Regenerative Medicine Platform Safety and Efficacy Hub, University of Liverpool, Liverpool, United Kingdom. FAU - Campana, Lara AU - Campana L AD - MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh, United Kingdom; Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom. FAU - Aleksieva, Niya AU - Aleksieva N AD - MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh, United Kingdom. FAU - Cartwright, Jennifer Ann AU - Cartwright JA AD - Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom. FAU - Mackinnon, Alison AU - Mackinnon A AD - Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom. FAU - O'Duibhir, Eoghan AU - O'Duibhir E AD - MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh, United Kingdom. FAU - Kendall, Timothy AU - Kendall T AD - Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom; Edinburgh Pathology, University of Edinburgh, Edinburgh, United Kingdom. FAU - Vermeren, Matthieu AU - Vermeren M AD - MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh, United Kingdom. FAU - Thomson, Adrian AU - Thomson A AD - Edinburgh Preclinical Imaging, BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom. FAU - Gadd, Victoria AU - Gadd V AD - MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh, United Kingdom. FAU - Dwyer, Benjamin AU - Dwyer B AD - MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh, United Kingdom. FAU - Aird, Rhona AU - Aird R AD - MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh, United Kingdom. FAU - Man, Tak-Yung AU - Man TY AD - MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh, United Kingdom. FAU - Rossi, Adriano Giorgio AU - Rossi AG AD - Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom. FAU - Forrester, Lesley AU - Forrester L AD - MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh, United Kingdom. FAU - Park, B Kevin AU - Park BK AD - UK Regenerative Medicine Platform Safety and Efficacy Hub, University of Liverpool, Liverpool, United Kingdom; MRC Centre for Drug Safety Science, University of Liverpool, Ashton Street, Liverpool, United Kingdom. FAU - Forbes, Stuart John AU - Forbes SJ AD - MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh, United Kingdom; UK Regenerative Medicine Platform Safety and Efficacy Hub, University of Liverpool, Liverpool, United Kingdom. Electronic address: stuart.forbes@ed.ac.uk. LA - eng GR - 095898/Z/11/Z/WT_/Wellcome Trust/United Kingdom GR - 203925/Z/16/A/WT_/Wellcome Trust/United Kingdom GR - MR/M007588/1/MRC_/Medical Research Council/United Kingdom GR - MC_PC_16043/MRC_/Medical Research Council/United Kingdom GR - 10896/Z/15/Z/WT_/Wellcome Trust/United Kingdom GR - MR/J010766/1/MRC_/Medical Research Council/United Kingdom GR - MRC/CIC5/06/MRC_/Medical Research Council/United Kingdom GR - MR/K017047/1/MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200311 PL - Netherlands TA - J Hepatol JT - Journal of hepatology JID - 8503886 RN - 0 (Cytokines) RN - 0 (Intercellular Signaling Peptides and Proteins) RN - 362O9ITL9D (Acetaminophen) SB - IM MH - Acetaminophen/*poisoning MH - Animals MH - Cell- and Tissue-Based Therapy/*methods MH - *Chemical and Drug Induced Liver Injury/immunology/metabolism/pathology MH - Cytokines/blood MH - Disease Models, Animal MH - Humans MH - Immunity, Innate MH - Intercellular Signaling Peptides and Proteins MH - Liver Regeneration/immunology MH - *Macrophages/immunology/metabolism MH - Mice MH - Paracrine Communication/*immunology MH - Phagocytosis MH - Treatment Outcome PMC - PMC7378576 OTO - NOTNLM OT - Acetaminophen OT - Liver regeneration OT - Macrophages OT - Necrosis OT - Phagocytosis COIS- Conflict of interest P.S.L., L.F., and S.J.F. have patents pending, entitled 'Macrophage-based therapy' in national territories of USA, Europe, Japan, China and Australia. These patents have been derived from PCT/GB2017/052769 filed 18/09/2017 and claim priority from UK application 1615923.8 filed 19/09/2016. Both of the original patents have now been abandoned because the original UK patent and PCT patent are no longer live and have now been replaced by the national patents. Please refer to the accompanying ICMJE disclosure forms for further details. EDAT- 2020/03/15 06:00 MHDA- 2021/11/04 06:00 PMCR- 2020/08/01 CRDT- 2020/03/15 06:00 PHST- 2019/09/17 00:00 [received] PHST- 2020/02/19 00:00 [revised] PHST- 2020/02/24 00:00 [accepted] PHST- 2020/03/15 06:00 [pubmed] PHST- 2021/11/04 06:00 [medline] PHST- 2020/03/15 06:00 [entrez] PHST- 2020/08/01 00:00 [pmc-release] AID - S0168-8278(20)30133-1 [pii] AID - 10.1016/j.jhep.2020.02.031 [doi] PST - ppublish SO - J Hepatol. 2020 Aug;73(2):349-360. doi: 10.1016/j.jhep.2020.02.031. Epub 2020 Mar 11.