Hepatic macrophages in liver injury and repair

doi:10.12092/j.issn.1009-2501.2018.10.016

Abstract

Abstract:

Hepatic macrophages play a critical role in the pathogenesis of liver injury and repair. It is noted that, based on the distinct origins and phenotypes, hepatic macrophages can clear bacterial pathogens, antigens, promote or inhibit the liver inflammation, which directly participate in the liver disease development and repair. This article reviews the functions and phenotypes of hepatic macrophages, and their roles in the different stages of liver injury and repair. Also, the potential macrophage-targeted therapies against liver diseases were also summarized.

Key words: hepatic macrophages, liver injury, liver repair, immunity

CLC Number:

WANG Lu, LI Liping, XING Xin, XU Dengqiu, XIAO Li, JIANG Zhenzhou, ZHANG Luyong, SUN Lixin. Hepatic macrophages in liver injury and repair[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2018, 23(10): 1188-1195.

References

［1］Gordon S. Elie Metchnikoff, the man and the myth［J］. J Innate Immun, 2016, 8(3): 223-227.
［2］Lee CH, Choi EY. Macrophages and inflammation［J］. J Rhrum Dis, 2018, 25(1): 11-18.
［3］Tabas I, Bornfeldt KE. Macrophage phenotype and function in different stages of atherosclerosis［J］. Circ Res, 2016, 118(4): 653-667.
［4］Gomez Perdiguero E, Klapproth K, Schulz C, et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors［J］. Nature, 2015, 518(7540): 547-551.
［5］夏园, 乔建林, 曾令宇. 组织固有巨噬细胞的研究进展［J］. 细胞与分子免疫学杂志, 2016, 32(7): 996-999.
［6］Hamidzadeh K, Christensen SM, Dalby E, et al. Macrophages and the recovery from acute and chronic inflammation［J］. Annu Rev Physiol, 2017, 79(1): 567-592.
［7］Mossanen JC, Krenkel O, Ergen C, et al. Chemokine (C-C motif) receptor 2-positive monocytes aggravate the early phase of acetaminophen induced acute liver injury［J］. Hepatology, 2016, 64(5): 1667-1682.
［8］Puengel T, Tacke F. Repair macrophages in acute liver failure［J］. Gut, 2017, 67(2): 202-203.
［9］白杨, 杨勇. 肝脏相关巨噬细胞起源及发育分化研究进展［J］. 药学研究, 2018, 37(1): 50-52.
［10］Gao B. Basic liver immunology［J］. Cell Mol Immunol, 2016, 13(3): 265-266.
［11］Sun YY, Li XF, Meng XM, et al. Macrophage phenotype in liver injury and repair［J］. Scand J Immunol, 2017, 85(3): 166-174.
［12］Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease［J］. Nature, 2013, 496(7446): 445-455.
［13］Cassado ADA, Lima MRDI, Bortoluci KR. Revisiting mouse peritoneal macrophages: Heterogeneity, development, and function［J］. Front Immunol, 2015, 6: 225.
［14］Wijesundera KK, Izawa T, Tennakoon AH, et al. M1- and M2-macrophage polarization in rat liver cirrhosis induced by thioacetamide (TAA), focusing on Iba1 and galectin-3［J］. Exp Mol Pathol, 2014, 96(3): 382-392.
［15］Zigmond E, Samia-Grinberg S, Pasmanik-Chor M, et al. Infiltrating monocyte-derived macrophages and resident kupffer cells display different ontogeny and functions in acute liver injury［J］. J Immunol, 2014, 193(1): 344-353.
［16］宛硕, 黄艳, 陈庭金, 等. 巨噬细胞极化的研究进展［J］. 中国病原生物学杂志, 2015, 10(11): 1051-1054.
［17］Dixon LJ, Barnes M, Tang H, et al. Kupffer cells in the liver［J］. Compr Physiol, 2013, 3(2): 785-797.
［18］Nguyen-Lefebvre AT, Horuzsko A. Kupffer cell metabolism and function［J］. J Enzymol Metab, 2015, 1(1): 101.
［19］Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas［J］. J Pathol, 2012, 229(2): 176-185.
［20］Shuang W, Meng XM, Ng YY, et al. TGF-β/Smad3 signalling regulates the transition of bone marrowderived macrophages into myofibroblasts during tissue fibrosis［J］. Oncotarget, 2016, 7(8): 8809-8822.
［21］Stables MJ, Shah S, Camon EB, et al. Transcriptomic analyses of murine resolution-phase macrophages［J］. Blood, 2011, 118(26): e192-e208.
［22］Ramachandran P, Pellicoro A, Vernon MA, et al. Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis［J］. Proc Natl Acad Sci U S A, 2012, 109(46): 3186-3195.
［23］Leung TM, Nieto N. CYP2E1 and oxidant stress in alcoholic and non-alcoholic fatty liver disease［J］. J Hepatol, 2013, 58(2): 395-398.
［24］Mandrekar P, Ambade A, Lim A, et al. An essential role for monocyte chemoattractant protein-1 in alcoholic liver injury: regulation of proinflammatory cytokines and hepatic steatosis in mice［J］. Hepatology, 2011, 54(6): 2185-2197.
［25］Wang M, You Q, Lor K, et al. Chronic alcohol ingestion modulates hepatic macrophage populations and functions in mice［J］. J Leukoc Biol, 2014, 96(4): 657-665.
［26］Zhao YY, Yang R, Xiao M, et al. Kupffer cells activation promoted binge drinking-induced fatty liver by activating lipolysis in white adipose tissues［J］. Toxicology, 2017, 390: 53-60.
［27］Lee J, French B, Morgan T, et al. The liver is populated by a broad spectrum of markers for macrophages. In alcoholic hepatitis the macrophages are M1 and M2［J］. Exp Mol Pathol, 2014, 96(1): 118-125.
［28］李丽萍, 邢欣, 王鹿, 等. 肝巨噬细胞在乙醇性脂肪肝发病过程中的作用研究进展［J］. 中国临床药理学杂志, 2017, 33(21): 2202-2205.
［29］娜日苏, 包纳日斯. 非酒精性脂肪肝的发病机制与流行病学的研究进展［J］. 中国医药指南, 2016, 14(3): 39-40.
［30］张云静, 宓余强. 非酒精性脂肪肝与肠道微生态的关系［J］. 肝脏, 2013, 18(5): 344-345.
［31］Reid DT, Reyes JL, McDonald BA, et al. Kupffer cells undergo fundamental changes during the development of experimental NASH and are critical in initiating liver damage and inflammation［J］. PLoS One, 2016, 11(7): e0159524.
［32］Luo W, Xu Q, Qi W, et al. Effect of modulation of PPAR-γ activity on Kupffer cells M1/M2 polarization in the development of non-alcoholic fatty liver disease［J］. Sci Rep, 2017, 7: 44612.
［33］王昭月, 卞兆连, 方一, 等. CCR2在非酒精性脂肪性肝炎中的表达及意义［J］. 肝脏, 2015, 20(5): 376-380.
［34］庄辉. 病毒性肝炎流行病学研究进展［J］. 中国继续医学教育, 2010, 2(3): 1-5.
［35］Chayama K, Hayes CN, Hiraga N, et al. Animal model for study of human hepatitis viruses［J］. J Gastroenterol Hepatol, 2011, 26(1): 13-18.
［36］Fangchao Y, Wenfeng Z, Di M, et al. Kupffer cell in the immune activation and tolerance toward HBV/HCV infection［J］. Adv Clin Exp Med, 2017, 26(4): 739-745.
［37］Gadd VL, Melino M, Roy S, et al. Portal, but not lobular, macrophages express matrix metalloproteinase-9: association with the ductular reaction and fibrosis in chronic hepatitis C［J］. Liver International, 2013, 33(4): 569-579.
［38］邢欣, 李丽萍, 王鹿, 等. 丙型病毒性肝炎中肝脏巨噬细胞的变化及作用［J］. 中国临床药理学与治疗学, 2017, 22(9): 1072-1076.
［39］Bility MT, Nio K, Li F, et al. Chronic hepatitis C infection-induced liver fibrogenesis is associated with M2 macrophage activation［J］. Sci Rep, 2016, 6: 39520.
［40］Ohtsuki T, Kimura K, Tokunaga Y, et al. M2 Macrophages play critical roles in progression of inflammatory liver disease in hepatitis C virus transgenic mice［J］. J Virol, 2016, 90(1): 300-307.
［41］Shrivastava S, Mukherjee A, Ray R, et al. Hepatitis C virus induces interleukin-1 beta (IL-1 beta)/IL-18 in circulatory and resident liver macrophages［J］. J Virol, 2013, 87(22): 12284-12290.
［42］Campana L, Iredale JP. Regression of liver fibrosis［J］. Semin Liver Dis, 2017, 37(1): 1.
［43］Wang Y, Shen RW, Han B, et al. Notch signaling mediated by TGF-β/Smad pathway in concanavalin A-induced liver fibrosis in rats［J］.World J Gastroenterol, 2017, 23(13): 2330-2336.
［44］Koyama Y, Brenner DA. Liver inflammation and fibrosis［J］. J Clin Invest, 2017, 127(1): 55-64.
［45］Locatelli L, Cadamuro M, Spirli C, et al. Macrophage recruitment by fibrocystin-defective biliary epithelial cells promotes portal fibrosis in congenital hepatic fibrosis［J］. Hepatology, 2016, 63(3): 965-982.
［46］Braga TT, Agudelo JSH, Camara NOS. Macrophages during the fibrotic process: M2 as friend and foe［J］. Front Immunol, 2015, 6: 602.
［47］Clichici S, Olteanu D, Nagy AL, et al. Silymarin inhibits the progression of fibrosis in the early stages of liver injury in CCl4-treated rats［J］. J Med Food, 2015, 18(3): 290-298.
［48］Craig AJ, Labgaa I, Villacorta-Martin C, et al. Tumor heterogeneity and resistance to targeted therapies in hepatocellular carcinoma［M］//Resistance to molecular therapies for hepatocellular carcinoma. Springer, Cham, 2017: 1-24.
［49］Downey CM, Aghaei M, Schwendener RA, et al. DMXAA causes tumor site-specific vascular disruption in murine non-small cell lung cancer, and like the endogenous non-canonical cyclic dinucleotide STING agonist, 2'3'-cGAMP, induces M2 macrophage repolarization［J］. PLoS One, 2014, 9(6): e99988.
［50］Ringelhan M, Pfister D, O'Connor T, et al. The immunology of hepatocellular carcinoma［J］. Nat Immunol, 2018: 1.
［51］陈伟, 周赟, 龚建平. 肿瘤相关巨噬细胞在原发性肝癌发生发展中的作用［J］. 临床肝胆病杂志, 2016, 32(7): 1422-1424.
［52］Wan S, Kuo N, Kryczek I, et al. Myeloid cells in hepatocellular carcinoma［J］. Hepatology, 2015, 62(4): 1304-1312.
［53］Schrammen PL, Bartneck M, Mockel D, et al. CCL2-dependent monocyte recruitment contributes to a tumor-promoting microenvironment in a combined fibrosis-HCC model［J］. J Hepatol, 2017, 66(1): S633.
［54］Krenkel O, Puengel T, Govaere O, et al. Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis［J］. Hepatology, 2018, 67(4): 1270-1283.
［55］Aoyama T, Inokuchi S, Brenner DA, et al. CX3CL1-CX3CR1 interaction prevents carbon tetrachloride-induced liver inflammation and fibrosis in mice［J］. Hepatology, 2010, 52(4): 1390-1400.
［56］Huang W, Metlakunta A, Dedousis N, et al. Depletion of liver Kupffer cells prevents the development of diet-induced hepatic steatosis and insulin resistance［J］. Diabetes, 2010, 59(2): 347-357.
［57］艾雄飞, 杜丹玉, 孙立, 等. 靶向肿瘤相关巨噬细胞的治疗进展及风险［J］. 中国临床药理学与治疗学, 2016, 21(6): 697-702.
［58］Dapito DH, Mencin A, Gwak GY, et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4［J］. Cancer Cell, 2012, 21(4): 504-516.
［59］Krenkel O, Tacke F. Liver macrophages in tissue homeostasis and disease［J］. Nat Rev Immunol, 2017, 17(5): 306-321.
［60］Loomba R, Lawitz E, Mantry PS, et al. GS-4997, an inhibitor of apoptosis signal-regulating kinase (ASK1), alone or in combination with simtuzumab for the treatment of nonalcoholic steatohepatitis (NASH): A randomized, phase 2 trial［J］. Hepatology, 2016, 64(6): 1119A-1120A.
［61］李校天, 尹燕, 郭永泽, 等. 1,25(OH)-2D-3干预IL-17及巨噬细胞炎性蛋白3α表达抑制大鼠肝纤维化形成的作用机制［J］. 临床肝胆病杂志, 2016, 32(12): 2331-2336.
［62］Negash AA, Ramos HJ, Crochet N, et al. IL-1 beta production through the NLRP3 inflammasome by hepatic macrophages links hepatitis C virus infection with liver inflammation and disease［J］. PLoS Pathog, 2013, 9(4): e1003330
［63］Ni YH, Fen ZG, Nagashimada M, et al. Novel action of carotenoids on non-alcoholic fatty liver disease: Macrophage polarization and liver homeostasis［J］. Nutrients, 2016, 8(7): 391.
［64］谢晓, 陆伦根. 非酒精性脂肪性肝病的潜在新疗法［J］. 临床肝胆病杂志, 2017, 33(12): 2439-2443.
［65］Farooque A, Afrin F, Adhikari JS, et al. Polarization of macrophages towards M1 phenotype by a combination of 2-deoxy-d-glucose and radiation: Implications for tumor therapy［J］. Immunobiology, 2015, 221(2): 269-281.
［66］Livingstone C. Successful Chinese German vollaborations in historical dresden［J］. Eur J Immunol, 2017, 47(3): 428-431.
［67］Rmh R, Coffelt SB, Neale TA, et al. PyMT-Maclow: A novel, inducible, murine model for determining the role of CD68 positive cells in breast tumor development［J］. PLoS One, 2017, 12(12): e0188591.
［68］Nguyen AL, Cao H, Thinn MM. Metastatic hepatocellular carcinoma treated with zoledronic acid［J］. J Oncol Pract, 2017, JOP.2017.023770.

[1]	XING Bomin, GUO Na, NING Haihui, DING Xinyun, MA Yuqing. Effects of Rho kinase inhibitors on septic liver injury [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2022, 27(5): 544-550.
[2]	LIU Wenjing, WU Zhitao, PAN Guoyu. Early dectection and prediction hepatotoxic risk in vitro [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2021, 26(8): 923-930.
[3]	SONG Ruzheng, PENG Ying, WANG Guangji, SUN Jianguo. Commonly used quantitative proteomics research techniques and their application in the study of pathogenesis of liver-derived diseases [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2021, 26(5): 570-578.
[4]	GAO Yan, LI Juntong, WU Qinglin, LI Lin, ZHANG Lan. Tetrahydroxy stilbene glycoside protects mice from acetaminophen-induced liver injury: study based on metabonomics [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2021, 26(2): 161-166.
[5]	XU Lina, LI Yue, PENG Jinyong. microRNA and drug-induced liver injury [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2020, 25(7): 803-809.
[6]	WANG Qian, SU Huizong, LI Yue, TAN Bo, YAN Dongming, JIN Jingyi, QIU Furong. Hepatoprotective effects of Yinchenzhufu decoction on intrahepatic cholestasis liver injury in mice induced by ANIT via suppressing TLR4/NF-κB pathway [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2020, 25(6): 601-609.
[7]	LI Hongli, WEN Dandan, BEI Chengli, GAO Lichen, PENG Xixu. Analysis of anti-tuberculosis drug induced liver injury and its drug use cost in the hospital before and after the special rectification [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2019, 24(9): 1030-1036.
[8]	MENG Qiuhua, TIAN Jing, QIN Feizhang, QIN Yang, DONG Min. Research progress of PD-1/PD-L1 pathway inhibitor in the immunotherapy of digestive system neoplasm [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2018, 23(8): 942-948.
[9]	LIAO Xiaoling，WU Liang，LIN Zongze，YE Jian. Lycopene protects against CCl₄-induced acute hepatic injury via inhibiting endoplasmic reticulum stress [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2018, 23(7): 770-775.
[10]	HAO Shaojun, MA Junjie, KONG Xuejun, SU Feng, LI Jun, LI Wenjun, ZHANG Zhengchen. Effects of compound Cotinus coggygria oral liquid on liver homogenate and liver tissue of rats [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2018, 23(6): 627-631.
[11]	ZHONG Zhengling，ZHANG Fei，JIANG Yuhua，ZHANG Weiting，TONG Jiucui，LI Juan，CHU Jiru，XIE Haitang. Protective effects of Ferulic acid on acute liver injury induced by D-GalN/LPS in mice [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2018, 23(12): 1335-1339.
[12]	WANG Yanhong, FENG Tiexin, PU Junfeng, ZHANG Lingfang, LI Hongling. Protective effects of manganese superoxide dismutase mimic on liver injury in mice induced by carbon tetrachloride [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2018, 23(11): 1209-1214.
[13]	RONG Guoyi, WANG Shumei, TANG Mo. Efficacy of reducing phlegm with traditional Chinese medicine on non-small cell lung cancer: a Meta-analysis [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2017, 22(7): 787-794.
[14]	LIU Hongjie, LI Tianhao, ZHAN Sha, CHEN Liang, CHEN Lingxiu, TANG Shujie. Effect and mechanism of acute liver injury induced by volatile oil from folium artemislae argyi in mice [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2017, 22(3): 248-252.
[15]	XU Saihua, HU Jingna, MEI Jingyan, MA Weicheng. Effects of Jiedu hugan granule on the inflammatory factor and tight junction protein of small intestine in rats with immunological liver injury [J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2017, 22(12): 1352-1357.