PMID- 28596109 OWN - NLM STAT- MEDLINE DCOM- 20180605 LR - 20181205 IS - 1600-0641 (Electronic) IS - 0168-8278 (Linking) VI - 67 IP - 4 DP - 2017 Oct TI - Cytotherapy with M1-polarized macrophages ameliorates liver fibrosis by modulating immune microenvironment in mice. PG - 770-779 LID - S0168-8278(17)32061-5 [pii] LID - 10.1016/j.jhep.2017.05.022 [doi] AB - BACKGROUND & AIMS: Macrophages play vital roles in chronic liver injury, and have been tested as a tool for cytotherapy in liver fibrosis. However, macrophages possess ontogenic and functional heterogeneities. Some subsets are pro-fibrotic, whereas others are anti-fibrotic. This study aimed to clarify which macrophage subset is efficient for cytotherapy in liver fibrosis and to elucidate the underlying mechanisms. METHODS: Liver fibrosis was induced in mice by carbon tetrachloride injection or bile duct ligation. Bone-marrow-derived macrophages (BMDMs) were polarized into M0, M1, or M2 macrophages, respectively. BMDMs were infused into mice through the tail vein at different stages of fibrogenesis. Fibrosis progression, hepatic cell populations, and related molecular changes were evaluated. RESULTS: Both M0 and M1 BMDMs significantly ameliorated liver fibrosis, but M1 exhibited stronger therapeutic effects than M0. M2 macrophages were not effective on liver fibrosis. M1 macrophages reduced the number and activation of hepatic stellate cells (HSCs), which could be attributed at least partly to increased HSC apoptosis. M1 macrophages enhanced the recruitment of endogenous macrophages into fibrotic liver, which displayed the phenotype of Ly6C(lo) restorative macrophages and produced matrix metalloproteinases (MMPs) and hepatic growth factor (HGF) to enhance collagen degradation and hepatocyte proliferation, respectively. M1 macrophages also increased the number of total and activated natural killer (NK) cells in the fibrotic liver, which released TNF-related apoptosis-inducing ligand (TRAIL), inducing HSC apoptosis. CONCLUSIONS: M1 macrophages, which modulate the immune microenvironment to recruit and modify the activation of endogenous macrophages and NK cells, are effective for cytotherapy in experimental liver fibrosis. Lay summary: M1 Bone marrow-derived macrophages (BMDMs) exhibit a stronger therapeutic effect by modulating the hepatic microenvironment to recruit and modify the activation of endogenous macrophages and natural killer (NK) cells, which likely lead to hepatic stellate cells (HSCs) apoptosis and hampered fibrogenesis. CI - Copyright (c) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. FAU - Ma, Peng-Fei AU - Ma PF AD - Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China; State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an 710032, China. FAU - Gao, Chun-Chen AU - Gao CC AD - State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an 710032, China. FAU - Yi, Jing AU - Yi J AD - State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an 710032, China. FAU - Zhao, Jun-Long AU - Zhao JL AD - State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an 710032, China. FAU - Liang, Shi-Qian AU - Liang SQ AD - State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an 710032, China. FAU - Zhao, Yang AU - Zhao Y AD - State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an 710032, China. FAU - Ye, Yu-Chen AU - Ye YC AD - Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China; State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an 710032, China. FAU - Bai, Jian AU - Bai J AD - State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an 710032, China. FAU - Zheng, Qi-Jun AU - Zheng QJ AD - State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an 710032, China. FAU - Dou, Ke-Feng AU - Dou KF AD - Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. Electronic address: doukef@fmmu.edu.cn. FAU - Han, Hua AU - Han H AD - Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China; State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an 710032, China. Electronic address: huahan@fmmu.edu.cn. FAU - Qin, Hong-Yan AU - Qin HY AD - State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an 710032, China. Electronic address: hyqin@fmmu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20170726 PL - Netherlands TA - J Hepatol JT - Journal of hepatology JID - 8503886 RN - 0 (Antigens, Ly) RN - 0 (Ly-6C antigen, mouse) RN - CL2T97X0V0 (Carbon Tetrachloride) SB - IM CIN - J Hepatol. 2018 May;68(5):1091-1093. PMID: 29317296 CIN - J Hepatol. 2018 May;68(5):1090-1091. PMID: 29317297 MH - Animals MH - Antigens, Ly/metabolism MH - Apoptosis MH - Carbon Tetrachloride/toxicity MH - Cell- and Tissue-Based Therapy/*methods MH - Cellular Microenvironment/immunology MH - Disease Models, Animal MH - Hepatic Stellate Cells/pathology MH - Killer Cells, Natural/immunology MH - Liver Cirrhosis/immunology/pathology/*therapy MH - Macrophage Activation MH - Macrophages/classification/*immunology/transplantation MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Transgenic OTO - NOTNLM OT - Cytotherapy OT - Hepatic stellate cells OT - Liver fibrosis OT - Macrophages OT - Polarization EDAT- 2017/06/10 06:00 MHDA- 2018/06/06 06:00 CRDT- 2017/06/10 06:00 PHST- 2016/12/03 00:00 [received] PHST- 2017/04/26 00:00 [revised] PHST- 2017/05/22 00:00 [accepted] PHST- 2017/06/10 06:00 [pubmed] PHST- 2018/06/06 06:00 [medline] PHST- 2017/06/10 06:00 [entrez] AID - S0168-8278(17)32061-5 [pii] AID - 10.1016/j.jhep.2017.05.022 [doi] PST - ppublish SO - J Hepatol. 2017 Oct;67(4):770-779. doi: 10.1016/j.jhep.2017.05.022. Epub 2017 Jul 26.