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

doi:10.3969/j.issn.1674-8115.2024.04.012

Abstract

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

CLC Number:

R575

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.

Figures/Tables 2

TrendMD

References 60

1	ASRANI S K, DEVARBHAVI H, EATON J, et al. Burden of liver diseases in the world[J]. J Hepatol, 2019, 70(1): 151-171.
2	VAN DER HEIDE D, WEISKIRCHEN R, BANSAL R. Therapeutic targeting of hepatic macrophages for the treatment of liver diseases[J]. Front Immunol, 2019, 10: 2852.
3	许钧, 金卫林, 李汛. 肝纤维化治疗的新视角: 靶向巨噬细胞代谢[J]. 临床肝胆病杂志, 2023, 39(4): 922-928.
	XU J, JIN W L, LI X. A new perspective for the treatment of liver fibrosis: targeting macrophage metabolism[J]. Journal of Clinical Hepatology, 2023, 39(4): 922-928.
4	YUNNA C, MENGRU H, LEI W, et al. Macrophage M1/M2 polarization[J]. Eur J Pharmacol, 2020, 877: 173090.
5	DOU L, SHI X M, HE X S, et al. Macrophage phenotype and function in liver disorder[J]. Front Immunol, 2020, 10: 3112.
6	汪鹏, 仇建南, 王忠夏, 等. 肝癌微环境中肿瘤相关巨噬细胞的研究进展[J]. 临床肝胆病杂志, 2023, 39(5): 1212-1218.
	WANG P, QIU J N, WANG Z X, et al. Research advances in tumor-associated macrophages in hepatocellular carcinoma microenvironment[J]. Journal of Clinical Hepatology, 2023, 39(5): 1212-1218.
7	SHAPOURI-MOGHADDAM A, MOHAMMADIAN S, VAZINI H, et al. Macrophage plasticity, polarization, and function in health and disease[J]. J Cell Physiol, 2018, 233(9): 6425-6440.
8	XIA T T, ZHANG M, LEI W, et al. Advances in the role of STAT3 in macrophage polarization[J]. Front Immunol, 2023, 14: 1160719.
9	LIU L L, GUO H M, SONG A M, et al. Progranulin inhibits LPS-induced macrophage M1 polarization via NF-κB and MAPK pathways[J]. BMC Immunol, 2020, 21(1): 32.
10	TAO L R, GUO G, QI Y Y, et al. Inhibition of canonical transient receptor potential 5 channels polarizes macrophages to an M1 phenotype[J]. Pharmacology, 2020, 105(3/4): 202-208.
11	ARPA L, BATLLE C, JIANG P J, et al. Distinct responses to IL4 in macrophages mediated by JNK[J]. Cells, 2023, 12(8): 1127.
12	CHEN W Y, LIU Y N, CHEN J, et al. The Notch signaling pathway regulates macrophage polarization in liver diseases[J]. Int Immunopharmacol, 2021, 99: 107938.
13	SHANAKI M, KHOSRAVI M, KHOSHDOONI-FARAHANI A, et al. High-intensity interval training reversed high-fat diet-induced M1-macrophage polarization in rat adipose tissue via inhibition of NOTCH signaling[J]. J Inflamm Res, 2020, 13: 165-174.
14	HU X R, HONG B Z, SHAN X X, et al. The effect of Poria cocos polysaccharide PCP-1C on M1 macrophage polarization via the Notch signaling pathway[J]. Molecules, 2023, 28(5): 2140.
15	YUAN C, YANG D D, MA J, et al. Modulation of Wnt/β-catenin signaling in IL-17A-mediated macrophage polarization of RAW264.7 cells[J]. Braz J Med Biol Res, 2020, 53(8): e9488.
16	杨晔妮, 赵梓吟, 王有鹏, 等. 缺氧肝癌源性外泌体miR-1260b对肿瘤相关巨噬细胞M2亚型的影响及其机制[J]. 精准医学杂志, 2023, 38(2): 105-110, 115.
	YANG Y N, ZHAO Z Y, WANG Y P, et al. Effects of hypoxic hepatoma-derived exosome miR-1260b on M2 macrophages and mechanism[J]. Journal of Precision Medicine, 2023, 38(2): 105-110, 115.
17	WANG Y, GAO R F, LI J P, et al. Downregulation of hsa_circ_0074854 suppresses the migration and invasion in hepatocellular carcinoma via interacting with HuR and via suppressing exosomes-mediated macrophage M2 polarization[J]. Int J Nanomedicine, 2021, 16: 2803-2818.
18	LI X, LEI Y, WU M, et al. Regulation of macrophage activation and polarization by HCC-derived exosomal lncRNA TUC339[J]. Int J Mol Sci, 2018, 19(10): 2958.
19	LI D, WANG C Q, MA P F, et al. PGC1α promotes cholangiocarcinoma metastasis by upregulating PDHA1 and MPC1 expression to reverse the Warburg effect[J]. Cell Death Dis, 2018, 9(5): 466.
20	王梦, 孙岳, 杨安宁, 等. 巨噬细胞PDHA1基因敲除对非酒精性脂肪性肝病小鼠肝细胞凋亡的影响[J]. 中国病理生理杂志, 2023, 39(1): 123-130.
	WANG M, SUN Y, YANG A N, et al. Effect of macrophage PDHA1 gene knockout on apoptosis of hepatocytes in mice with non-alcoholic fatty liver disease[J]. Chinese Journal of Pathophysiology, 2023, 39(1): 123-130.
21	CHENG J W, CAI W W, ZONG S Y, et al. Metabolite transporters as regulators of macrophage polarization[J]. Naunyn Schmiedeberg's Arch Pharmacol, 2022, 395(1): 13-25.
22	MA D, ZHOU X, WANG Y, et al. Changes in the small noncoding RNAome during M1 and M2 macrophage polarization[J]. Front Immunol, 2022, 13: 799733.
23	GUO Q, ZHU X X, WEI R, et al. MiR-130b-3p regulates M1 macrophage polarization via targeting IRF1[J]. J Cell Physiol, 2021, 236(3): 2008-2022.
24	HUANG Y, DU K L, GUO P Y, et al. IL-16 regulates macrophage polarization as a target gene of miR-145-3p[J]. Mol Immunol, 2019, 107: 1-9.
25	GHAFOURI-FARD S, ABAK A, TAVAKKOLI AVVAL S, et al. The impact of non-coding RNAs on macrophage polarization[J]. Biomed Pharmacother, 2021, 142: 112112.
26	LIU D L, WEI Y H, LIU Y D, et al. The long non-coding RNA NEAT1/miR-224-5p/IL-33 axis modulates macrophage M2a polarization and A1 astrocyte activation[J]. Mol Neurobiol, 2021, 58(9): 4506-4519.
27	WU S Q, XU R, ZHU X, et al. The long noncoding RNA LINC01140/miR-140-5p/FGF9 axis modulates bladder cancer cell aggressiveness and macrophage M2 polarization[J]. Aging, 2020, 12(24): 25845-25864.
28	ROOKS M G, GARRETT W S. Gut microbiota, metabolites and host immunity[J]. Nat Rev Immunol, 2016, 16(6): 341-352.
29	WANG Y, LIU H W, ZHAO J S. Macrophage polarization induced by probiotic bacteria: a concise review[J]. Probiotics Antimicrob Proteins, 2020, 12(3): 798-808.
30	JANG S E, HYAM S R, HAN M J, et al. Lactobacillus brevis G-101 ameliorates colitis in mice by inhibiting NF-κB, MAPK and AKT pathways and by polarizing M1 macrophages to M2-like macrophages[J]. J Appl Microbiol, 2013, 115(3): 888-896.
31	GUHA D, BANERJEE A, MUKHERJEE R, et al. A probiotic formulation containing Lactobacillus bulgaricus DWT1 inhibits tumor growth by activating pro-inflammatory responses in macrophages[J]. J Funct Foods, 2019, 56: 232-245.
32	GU J H, HE X Z, CHEN X Y, et al. Effects of electrical stimulation on cytokine-induced macrophage polarization[J]. J Tissue Eng Regen Med, 2022, 16(5): 448-459.
33	YANG Y, NI M, ZONG R B, et al. Targeting Notch1-YAP circuit reprograms macrophage polarization and alleviates acute liver injury in mice[J]. Cell Mol Gastroenterol Hepatol, 2023, 15(5): 1085-1104.
34	WANG Q, WEI S, ZHOU H M, et al. Hyperglycemia exacerbates acetaminophen-induced acute liver injury by promoting liver-resident macrophage proinflammatory response via AMPK/PI3K/AKT-mediated oxidative stress[J]. Cell Death Discov, 2019, 5: 119.
35	JIN G L, LIU H P, HUANG Y X, et al. Koumine regulates macrophage M1/M2 polarization via TSPO, alleviating sepsis-associated liver injury in mice[J]. Phytomedicine, 2022, 107: 154484.
36	CHEN Q, SONG Y T, YANG N L, et al. Aging deteriorated liver Ischemia and reperfusion injury by suppressing Tribble's proteins 1 mediated macrophage polarization[J]. Bioengineered, 2022, 13(6): 14519-14533.
37	LAN Y, QIAN B, HUANG H Y, et al. Hepatocyte-derived prostaglandin E2-modulated macrophage M1-type polarization via mTOR-NPC1 axis-regulated cholesterol transport from lysosomes to the endoplasmic reticulum in hepatitis B virus x protein-related nonalcoholic steatohepatitis[J]. Int J Mol Sci, 2022, 23(19): 11660.
38	VOLAREVIC V, MILOVANOVIC M, LJUJIC B, et al. Galectin-3 deficiency prevents concanavalin A-induced hepatitis in mice[J]. Hepatology, 2012, 55(6): 1954-1964.
39	CHI G, PEI J H, LI X Q. EZH2-mediated H3K27me3 promotes autoimmune hepatitis progression by regulating macrophage polarization[J]. Int Immunopharmacol, 2022, 106: 108612.
40	LIU Y, LIU H, ZHU J S, et al. Interleukin-34 drives macrophage polarization to the M2 phenotype in autoimmune hepatitis[J]. Pathol Res Pract, 2019, 215(8): 152493.
41	WAN Y M, WU H M, LI Y H, et al. TSG-6 inhibits oxidative stress and induces M2 polarization of hepatic macrophages in mice with alcoholic hepatitis via suppression of STAT3 activation[J]. Front Pharmacol, 2020, 11: 10.
42	LI J H, YU M X, ZONG R B, et al. Deacetylation of Notch1 by SIRT1 contributes to HBsAg- and HBeAg-mediated M2 macrophage polarization[J]. Am J Physiol Gastrointest Liver Physiol, 2022, 322(4): G459-G471.
43	AFFO S, YU L X, SCHWABE R F. The role of cancer-associated fibroblasts and fibrosis in liver cancer[J]. Annu Rev Pathol, 2017, 12: 153-186.
44	LEE C B, KIM M, HAN J, et al. Mesenchymal stem cells influence activation of hepatic stellate cells, and constitute a promising therapy for liver fibrosis[J]. Biomedicines, 2021, 9(11): 1598.
45	AYDIN M M, AKCALI K C. Liver fibrosis[J]. Turk J Gastroenterol, 2018, 29(1): 14-21.
46	黄莎莎, 邹艳丽, 谭洁, 等. CX3CR1沉默介导的巨噬细胞极化减轻CCl₄诱导的小鼠肝纤维化[J]. 陆军军医大学学报, 2022, 44(13): 1314-1321.
	HUANG S S, ZOU Y L, TAN J, et al. CX3CR1 silencing-mediated macrophage polarization attenuates CCl₄-induced liver fibrosis in mice[J]. Journal of Army Medical University, 2022, 44(13): 1314-1321.
47	TAO R, HAN M W, YUAN W, et al. Fibrinogen-like protein 2 promotes proinflammatory macrophage polarization and mitochondrial dysfunction in liver fibrosis[J]. Int Immunopharmacol, 2023, 117: 109631.
48	PENG Y, LI Z D, CHEN S, et al. DHFR silence alleviated the development of liver fibrosis by affecting the crosstalk between hepatic stellate cells and macrophages[J]. J Cell Mol Med, 2021, 25(21): 10049-10060.
49	WREE A, MARRA F. The inflammasome in liver disease[J]. J Hepatol, 2016, 65(5): 1055-1056.
50	FENG M, DING J, WANG M, et al. Kupffer-derived matrix metalloproteinase-9 contributes to liver fibrosis resolution[J]. Int J Biol Sci, 2018, 14(9): 1033-1040.
51	RAMACHANDRAN P, PELLICORO A, VERNON M A, et al. Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis[J]. Proc Natl Acad Sci USA, 2012, 109(46): E3186-E3195.
52	ELSHERIF S A, ALM A S. Role of macrophages in liver cirrhosis: fibrogenesis and resolution[J]. Anat Cell Biol, 2022, 55(1): 14-19.
53	LV S M, WANG J H, LI L. Extracellular vesicular lncRNA FAL1 promotes hepatocellular carcinoma cell proliferation and invasion by inducing macrophage M2 polarization[J]. J Physiol Biochem, 2023, 79(3): 669-682.
54	MENG Q, DUAN X Y, YANG Q C, et al. SLAMF6/Ly108 promotes the development of hepatocellular carcinoma via facilitating macrophage M2 polarization[J]. Oncol Lett, 2022, 23(3): 83.
55	KOHLHEPP M S, LIU H Y, TACKE F, et al. The contradictory roles of macrophages in non-alcoholic fatty liver disease and primary liver cancer: challenges and opportunities[J]. Front Mol Biosci, 2023, 10: 1129831.
56	YANG L F, ZHANG Z B, WANG L. S100A9 promotes tumor-associated macrophage for M2 macrophage polarization to drive human liver cancer progression: an in vitro study[J]. Kaohsiung J Med Sci, 2023, 39(4): 345-353.
57	谢昌利, 郭变琴, 刘翠颖, 等. 内源性β干扰素维持M1型巨噬细胞极化状态抑制肝癌细胞增殖和侵袭[J]. 细胞与分子免疫学杂志, 2016, 32(7): 865-869, 875.
	XIE C L, GUO B Q, LIU C Y, et al. Endogenous IFN-β maintains M1 polarization status and inhibits proliferation and invasion of hepatocellular carcinoma cells[J]. Chinese Journal of Cellular and Molecular Immunology, 2016, 32(7): 865-869, 875.
58	谢昌利, 刘翠颖, 林艳, 等. IRF1对M1巨噬细胞极化及其抗肿瘤效应的影响[J]. 基础医学与临床, 2017, 37(2): 189-196.
	XIE C L, LIU C Y, LIN Y, et al. Effect of IRF1 on polarization and antitumor function of M1 microphage[J]. Basic and Clinical Medicine, 2017, 37(2): 189-196.
59	PAVLOVIĆ N, KOPSIDA M, GERWINS P, et al. Inhibiting P2Y12 in macrophages induces endoplasmic reticulum stress and promotes an anti-tumoral phenotype[J]. Int J Mol Sci, 2020, 21(21): 8177.
60	HU Z Q, ZHANG H, LIU W, et al. Mechanism of HBV-positive liver cancer cell exosomal miR-142-3p by inducing ferroptosis of M1 macrophages to promote liver cancer progression[J]. Transl Cancer Res, 2022, 11(5): 1173-1187.

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

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

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