Cytotherapy with M1-polarized macrophages ameliorates liver fibrosis by modulating immune microenvironment in mice
Cytotherapy with M1-polarized macrophages ameliorates liver fibrosis by modulating immune microenvironment in mice
复制标题
M1极化巨噬细胞细胞疗法通过调节小鼠免疫微环境改善肝纤维化
DOI：
10.1016/j.jhep.2017.05.022
复制
发表时间：
2017-10-01
影响因子：
25.7
通讯作者：
Qin, Hong-Yan
中科院分区：
文献类型：
--
作者：
Ma, Peng-Fei;Gao, Chun-Chen;Qin, Hong-Yan
背景与目的：巨噬细胞在慢性肝损伤中起着至关重要的作用，并且已作为肝纤维化细胞治疗的一种工具进行了试验。然而，巨噬细胞具有个体发生和功能的异质性。一些亚群是促纤维化的，而另一些则是抗纤维化的。本研究旨在阐明哪种巨噬细胞亚群对肝纤维化的细胞治疗有效，并阐明其潜在机制。
方法：通过四氯化碳注射或胆管结扎在小鼠中诱导肝纤维化。骨髓来源的巨噬细胞（BMDMs）分别极化为M0、M1或M2巨噬细胞。在肝纤维化形成的不同阶段通过尾静脉将BMDMs注入小鼠体内。评估纤维化进展、肝细胞群以及相关的分子变化。
结果：M0和M1型BMDMs均显著改善了肝纤维化，但M1表现出比M0更强的治疗效果。M2巨噬细胞对肝纤维化无效。M1巨噬细胞减少了肝星状细胞（HSCs）的数量和活化，这至少部分可归因于HSC凋亡增加。M1巨噬细胞增强了内源性巨噬细胞向纤维化肝脏的募集，这些内源性巨噬细胞表现出Ly6C（lo）修复性巨噬细胞的表型，并产生基质金属蛋白酶（MMPs）和肝细胞生长因子（HGF），分别促进胶原降解和肝细胞增殖。M1巨噬细胞还增加了纤维化肝脏中总自然杀伤（NK）细胞和活化NK细胞的数量，它们释放肿瘤坏死因子相关凋亡诱导配体（TRAIL），诱导HSC凋亡。
结论：M1巨噬细胞通过调节免疫微环境以募集和改变内源性巨噬细胞和NK细胞的活化，对实验性肝纤维化的细胞治疗是有效的。
通俗总结：M1骨髓来源的巨噬细胞（BMDMs）通过调节肝脏微环境以募集和改变内源性巨噬细胞和自然杀伤（NK）细胞的活化，表现出更强的治疗效果，这可能导致肝星状细胞（HSCs）凋亡并阻碍纤维化形成。（C）2017欧洲肝脏研究协会。由爱思唯尔B.V.出版。保留所有权利。
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. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.