巨噬细胞M1/M2型极化在不同肝病中的作用研究进展

doi:10.3969/j.issn.1674-8115.2024.04.012

上海交通大学学报（医学版） ›› 2024, Vol. 44 ›› Issue (4): 509-517.doi: 10.3969/j.issn.1674-8115.2024.04.012

• 综述 • 上一篇

巨噬细胞M1/M2型极化在不同肝病中的作用研究进展

牛媛媛¹(), 汪龙德²(), 胥文娟³, 李正菊¹, 张瑞婷¹, 吴毓谦¹

^1.甘肃中医药大学中医临床学院，兰州 730000
^2.甘肃中医药大学附属医院消化科，兰州 730000
^3.甘肃省中医院针灸三科，兰州 730050

收稿日期:2023-09-13 接受日期:2024-03-19 出版日期:2024-04-28 发布日期:2024-04-28
通讯作者: 汪龙德 E-mail:1067748351@qq.com;wwlldd666@163.com
作者简介:牛媛媛（1994—），女，住院医师，博士生；电子信箱：1067748351@qq.com。
基金资助:
国家自然科学基金(82160883);2022年度甘肃省中医药科研立项课题(GZKZ-2022-5);兰州市城关区2021年科技计划项目(2021-9-2);2022年兰州市科技计划项目(2022-3-26);2023年甘肃省教育厅优秀研究生“创新之星”项目(2023CXZX-731)

Research progress in the role of M1/M2 polarization of macrophages in different liver diseases

NIU Yuanyuan¹(), WANG Longde²(), XU Wenjuan³, LI Zhengju¹, ZHANG Ruiting¹, WU Yuqian¹

^1.Clinical College of Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, China
^2.Department of Gastroenterology, Affiliated Hospital of Gansu University of Chinese Medicine, Lanzhou 730000, China
^3.Third Department of Acupuncture and Moxibustion, Gansu Provincial Hospital of Traditional Chinese Medicine, Lanzhou 730050, China

Received:2023-09-13 Accepted:2024-03-19 Online:2024-04-28 Published:2024-04-28
Contact: WANG Longde E-mail:1067748351@qq.com;wwlldd666@163.com
Supported by:
National Natural Science Foundation of China(82160883);Gansu Province Traditional Chinese Medicine Research Project in 2022(GZKZ-2022-5);Science and Technology Plan Project of Chengguan District of Lanzhou in 2021(2021-9-2);Science and Technology Plan Project of Lanzhou in 2022(2022-3-26);Excellent Graduate Student "Innovation Star" Project of Gansu Provincial Department of Education in 2023(2023CXZX-731)

摘要/Abstract

摘要：

巨噬细胞具有较强的可塑性与异质性，可针对不同信号刺激发生功能转化，如转化为经典激活M1型（即M1型极化）、选择性激活M2型（即M2型极化）等。巨噬细胞M1/M2型极化的途径较为广泛，涉及核因子-κB（nuclear factor-κB，NF-κB）/丝裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）信号通路、白细胞介素-4（interleukin-4，IL-4）/信号转导与转录激活因子6（signal transduction and activator of transcription 6，STAT6）信号通路、Notch信号通路、无翼样糖蛋白/β-连环蛋白（Wnt/β-catenin）信号通路等。同时，巨噬细胞M1/M2型极化可不同程度地受到外泌体、代谢物、非编码RNA、电刺激、益生菌等的功能调节，其失衡与不同类型肝病的发生、发展关系密切。该文通过对该极化的作用机制进行梳理，发现巨噬细胞M1型极化在肝组织损伤、炎症反应及纤维化进程中起助推作用，巨噬细胞M2型极化则相反；其中，肝癌作为慢性肝病的晚期阶段，以巨噬细胞M2型极化增强、巨噬细胞M1型极化受损为特征。因此，该文关注巨噬细胞M1/M2型极化在不同类型肝病中的作用，以期能更好地确立巨噬细胞亚群靶向疗法。

关键词: 巨噬细胞极化, M1型巨噬细胞, M2型巨噬细胞, 肝脏疾病

Abstract:

Macrophages have strong plasticity and heterogeneity, and can undergo functional transformation in response to different signal stimuli, such as classical activation of M1 type (M1 type polarization) and selective activation of M2 type (M2 type polarization). The pathways of macrophage M1/M2 polarization are quite extensive, involving nuclear factor-κB (NF-κB)/mitogen-activated protein kinase (MAPK) signaling pathway, interleukin-4 (IL-4)/signal transduction and activator of transcription 6 (STAT6) signaling pathway, Notch signaling pathway, Wnt/β-catenin signaling pathway, etc. At the same time, M1/M2 polarization of macrophages is also regulated by exosomes, metabolites, non-coding RNA, electrical stimulation, probiotics, etc., and its imbalance is closely related to the occurrence and development of different types of liver disease. In this paper, the mechanism of its polarization was reviewed, and it was found that M1 polarization of macrophages played a promoting role in the process of liver tissue injury, inflammation and fibrosis, while M2 polarization of macrophages played the opposite role. Among them, hepatocellular carcinoma, as the advanced stage of chronic liver disease, was characterized by increased M2 polarization and impaired M1 polarization of macrophages. Therefore, this paper pays attention to the role of M1/M2 polarization of macrophages in different types of liver diseases, in order to better establish the targeted therapy of macrophage subsets.

Key words: macrophage polarization, M1 macrophage, M2 macrophage, liver disease

中图分类号:

R575

牛媛媛, 汪龙德, 胥文娟, 李正菊, 张瑞婷, 吴毓谦. 巨噬细胞M1/M2型极化在不同肝病中的作用研究进展[J]. 上海交通大学学报（医学版）, 2024, 44(4): 509-517.

NIU Yuanyuan, WANG Longde, XU Wenjuan, LI Zhengju, ZHANG Ruiting, WU Yuqian. Research progress in the role of M1/M2 polarization of macrophages in different liver diseases[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(4): 509-517.

图/表 2

表1 巨噬细胞极化的表型分类、诱导剂、细胞因子分泌、生物标志物、信号通路及功能作用

Tab 1 Phenotypic classification， inducers， cytokine secretion， biomarkers， signaling pathways and functional characteristics of macrophage polarization

Macrophage polarization type	Inducer	Cytokine secretion	Biomarker	Signaling pathways affecting polarization	Functional characteristics
M1 macrophage	LPS, IFN-γ	IL-6, IL-12, IL-1β, TNF-α, NO, GFAP, iNOS	CD80, CD86, CD16/32	NF-κB, MAPK, Wnt/ β-catenin, Notch	Antigen-presenting, mediating Th1 and Th17 immune responses, proinflammatory, anti-tumor, eliminating pathogens
M2a macrophage	IL-4, IL-13	Arg-1, CCL17, IL-10, CCL22	CD206, CD103	IL-4/STAT6, MAPK, JNK-1/STAT6	Anti-inflammatory, mediating Th2 type immune response, tissue repair, allergy, fibrotic immune regulation
M2b macrophage	IL-33, LPS	IL-10, TNF-α, IL-6, TGF-β, VEGF	CD206, MHCⅡ	TLR4, PI3K
M2c macrophage	TGF-β, IL-10	Arg-1, TGF-β, CXCL13	CD163, CD206	JAK/STAT3, NF-κB, TGF-β/Smads	Phagocytosis, immunosuppression
M2d macrophage	TLR agonist	IL-10, VEGF, IL-12^low, TNF-α^low	CD206	TLR4, NF-κB	Organizational restructuring, angiogenesis

图1 巨噬细胞M1/M2型极化参与不同类型肝脏疾病的作用机制Note： NASH—non-alcoholic steatohepatitis; MCP-1—monocyte chemoattractant protein-1; AMPK—AMP-activated protein kinase; PKB—protein kinase B, also known as AKT; PGE2—prostaglandin E2; EP4—prostaglandin E2 receptor 4; mTOR—mammalian target of rapamycin; NPC1—niemann-pick C1; FGL2—fibrinogen-like protein 2; HSP90—heat shock protein 90; DHFR—dihydrofolate reductase; mtROS—mitochondrial reactive oxygen species; FoxO1—forkhead box protein O1; CCR4—C-C chemokine receptor 4; SLAMF6—signaling lymphocytic activation molecule family member 6; TSPO—translocator protein; YAP—Yes-associated protein; TSG-6—tumor necrosis factor alpha-stimulated gene/inducible protein 6; SIRT1—silent information regulator 1; MMP9—matrix metalloproteinase 9; IGF-1—insulin-like growth factor 1.

Fig 1 Mechanism of M1/M2 polarization of macrophages involved in different types of liver diseases

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巨噬细胞M1/M2型极化在不同肝病中的作用研究进展

Research progress in the role of M1/M2 polarization of macrophages in different liver diseases

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