Anat Cell Biol.  2022 Mar;55(1):14-19. 10.5115/acb.21.046.

Role of macrophages in liver cirrhosis: fibrogenesis and resolution

• Elsherif SA
• Alm AS

• KMID: 2527664
• DOI: http://doi.org/10.5115/acb.21.046

Abstract

At present, chronic liver disease accounts for approximately 2 million deaths per year worldwide. Liver injury induces a series of events causing inflammation. Chronic inflammation ends in liver fibrosis. A stage of fibrinolysis occurs on stopping insult. Kupffer cells play their role to initiate inf lammatory responses, while infiltrating monocyte-derived macrophages have a role both in chronic inf lammation and fibrosis and in fibrosis resolution. Ly-6C high expressing monocytes act during fibrogenesis, while Ly-6C low expressing monocytes are restorative macrophages which promote resolution of fibrosis after end of the injury. Recent studies have identified new phenotypes, such as metabolically activated M, oxidized, which may have a role in fatty liver diseases.

Keyword

Liver cirrhosis; Macrophages; Fibrosis; Liver cirrhosis; Macrophages

Reference

References

1. Asrani SK, Devarbhavi H, Eaton J, Kamath PS. 2019; Burden of liver diseases in the world. J Hepatol. 70:151–71. DOI: 10.1016/j.jhep.2018.09.014. PMID: 30266282.

2. Tanwar S, Rhodes F, ivastava A Sr, Trembling PM, Rosenberg WM. 2020; Inflammation and fibrosis in chronic liver diseases including non-alcoholic fatty liver disease and hepatitis C. World J Gastroenterol. 26:109–33. DOI: 10.3748/wjg.v26.i2.109. PMID: 31969775. PMCID: PMC6962431.

3. Alharthi J, Latchoumanin O, George J, Eslam M. 2020; Macrophages in metabolic associated fatty liver disease. World J Gastroenterol. 26:1861–78. DOI: 10.3748/wjg.v26.i16.1861. PMID: 32390698. PMCID: PMC7201150.

4. Kazankov K, Barrera F, Møller HJ, Rosso C, Bugianesi E, David E, Younes R, Esmaili S, Eslam M, McLeod D, Bibby BM, Vilstrup H, George J, Grønbaek H. 2016; The macrophage activation marker sCD163 is associated with morphological disease stages in patients with non-alcoholic fatty liver disease. Liver Int. 36:1549–57. DOI: 10.1111/liv.13150. PMID: 27102725.

5. Martinez FO, Gordon S. 2014; The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 6:13.

6. Tacke F, Zimmermann HW. 2014; Macrophage heterogeneity in liver injury and fibrosis. J Hepatol. 60:1090–6. DOI: 10.12703/p6-13. DOI: 10.1016/j.jhep.2013.12.025. PMID: 24412603.

7. Baeck C, Wei X, Bartneck M, Fech V, Heymann F, Gassler N, Hittatiya K, Eulberg D, Luedde T, Trautwein C, Tacke F. 2014; Pharmacological inhibition of the chemokine C-C motif chemokine ligand 2 (monocyte chemoattractant protein 1) accelerates liver fibrosis regression by suppressing Ly-6C(+) macrophage infiltration in mice. Hepatology. 59:1060–72. DOI: 10.3410/f.718259135.793492238. PMID: 24481979.

8. Tacke F. 2017; Targeting hepatic macrophages to treat liver diseases. J Hepatol. 66:1300–12. DOI: 10.1016/j.jhep.2017.02.026. PMID: 28267621.

9. Dong X, Liu J, Xu Y, Cao H. 2019; Role of macrophages in experimental liver injury and repair in mice. Exp Ther Med. 17:3835–47. DOI: 10.3892/etm.2019.7450. PMID: 31007731. PMCID: PMC6468932.

10. Wree A, Marra F. 2016; The inflammasome in liver disease. J Hepatol. 65:1055–6. DOI: 10.1016/j.jhep.2016.07.002. PMID: 27660175.

11. Weber LW, Boll M, Stampfl A. 2003; Hepatotoxicity and mechanism of action of haloalkanes: carbon tetrachloride as a toxicological model. Crit Rev Toxicol. 33:105–36. DOI: 10.1080/713611034. PMID: 12708612.

12. Marra F, Tacke F. 2014; Roles for chemokines in liver disease. Gastroenterology. 147:577–94.e1. DOI: 10.1053/j.gastro.2014.06.043. PMID: 25066692.

13. Chu PS, Nakamoto N, Ebinuma H, Usui S, Saeki K, Matsumoto A, et al. 2013; C-C motif chemokine receptor 9 positive macrophages activate hepatic stellate cells and promote liver fibrosis in mice. Hepatology. 58:337–50. DOI: 10.1002/hep.26351. PMID: 23460364.

14. Li Y, Schwabe RF, DeVries-Seimon T, Yao PM, Gerbod-Giannone MC, Tall AR, Davis RJ, Flavell R, Brenner DA, Tabas I. 2005; Free cholesterol-loaded macrophages are an abundant source of tumor necrosis factor-alpha and interleukin-6: model of NF-kappaB- and map kinase-dependent inflammation in advanced atherosclerosis. J Biol Chem. 280:21763–72. DOI: 10.1074/jbc.M501759200. PMID: 15826936.

15. Pradere JP, Kluwe J, De Minicis S, Jiao JJ, Gwak GY, Dapito DH, Jang MK, Guenther ND, Mederacke I, Friedman R, Dragomir AC, Aloman C, Schwabe RF. 2013; Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice. Hepatology. 58:1461–73. DOI: 10.1002/hep.26429.

16. Ramachandran P, Iredale JP, Fallowfield JA. 2015; Resolution of liver fibrosis: basic mechanisms and clinical relevance. Semin Liver Dis. 35:119–31. DOI: 10.1055/s-0035-1550057. PMID: 25974898.

17. Ramachandran P, Pellicoro A, Vernon MA, Boulter L, Aucott RL, Ali A, Hartland SN, Snowdon VK, Cappon A, Gordon-Walker TT, Williams MJ, Dunbar DR, Manning JR, van Rooijen N, Fallowfield JA, Forbes SJ, Iredale JP. 2012; Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis. Proc Natl Acad Sci U S A. 109:E3186–95. DOI: 10.1073/pnas.1119964109. PMID: 23100531. PMCID: PMC3503234.

18. Fallowfield JA, Mizuno M, Kendall TJ, Constandinou CM, Benyon RC, Duffield JS, Iredale JP. 2007; Scar-associated macrophages are a major source of hepatic matrix metalloproteinase-13 and facilitate the resolution of murine hepatic fibrosis. J Immunol. 178:5288–95. DOI: 10.4049/jimmunol.178.8.5288. PMID: 17404313.

19. Beattie L, Sawtell A, Mann J, Frame TCM, Teal B, de Labastida Rivera F, Brown N, Walwyn-Brown K, Moore JWJ, MacDonald S, Lim EK, Dalton JE, Engwerda CR, MacDonald KP, Kaye PM. 2016; Bone marrow-derived and resident liver macrophages display unique transcriptomic signatures but similar biological functions. J Hepatol. 65:758–68. DOI: 10.1016/j.jhep.2016.05.037. PMID: 27262757. PMCID: PMC5028381.

20. Sakai M, Troutman TD, Seidman JS, Ouyang Z, Spann NJ, Abe Y, Ego KM, Bruni CM, Deng Z, Schlachetzki JCM, Nott A, Bennett H, Chang J, Vu BT, Pasillas MP, Link VM, Texari L, Heinz S, Thompson BM, McDonald JG, Geissmann F, Glass CK. 2019; Liver-derived signals sequentially reprogram myeloid enhancers to initiate and maintain Kupffer cell identity. Immunity. 51:655–70.e8. DOI: 10.1016/j.immuni.2019.09.002. PMID: 31587991. PMCID: PMC6800814.

21. Wang J, Kubes P. 2016; A reservoir of mature cavity macrophages that can rapidly invade visceral organs to affect tissue repair. Cell. 163:668–78. DOI: 10.1016/j.cell.2016.03.009. PMID: 27062926.

22. Li L, Wei W, Li Z, Chen H, Li Y, Jiang W, Chen W, Kong G, Yang J, Li Z. 2018; The spleen promotes the secretion of CCL2 and supports an M1 dominant phenotype in hepatic macrophages during liver fibrosis. Cell Physiol Biochem. 51:557–74. DOI: 10.33594/000000112. PMID: 30458454. PMID: d17af1d8643b47d29f20a293f2992e02.

23. Orekhov AN, Orekhova VA, Nikiforov NG, Myasoedova VA, Grechko AV, Romanenko EB, Zhang D, Chistiakov DA. 2019; Monocyte differentiation and macrophage polarization. Vessel Plus. 3:10. DOI: 10.20517/2574-1209.2019.04.

24. Graubardt N, Vugman M, Mouhadeb O, Caliari G, Pasmanik-Chor M, Reuveni D, Zigmond E, Brazowski E, David E, Chappell-Maor L, Jung S, Varol C. 2017; Ly6Chi monocytes and their macrophage descendants regulate neutrophil function and clearance in acetaminophen-induced liver injury. Front Immunol. 8:626. DOI: 10.3389/fimmu.2017.00626. PMID: 28620383. PMCID: PMC5451509.

25. Song P, Zhang J, Zhang Y, Shu Z, Xu P, He L, Yang C, Zhang J, Wang H, Li Y, Li Q. 2018; Hepatic recruitment of CD11b+Ly6C+ inflammatory monocytes promotes hepatic ischemia/reperfusion injury. Int J Mol Med. 41:935–45. DOI: 10.3892/ijmm.2017.3315. PMID: 29251315. PMCID: PMC5752159.

26. Zheng Z, Wang H, Li L, Zhang S, Zhang C, Zhang H, Ji F, Liu X, Zhu K, Kong G, Li Z. 2020; Splenectomy enhances the Ly6Clow phenotype in hepatic macrophages by activating the ERK1/2 pathway during liver fibrosis. Int Immunopharmacol. 86:106762. DOI: 10.1016/j.intimp.2020.106762. PMID: 32652503.

27. Wong KL, Tai JJ, Wong WC, Han H, Sem X, Yeap WH, Kourilsky P, Wong SC. 2011; Gene expression profiling reveals the defining features of the classical, intermediate, and nonclassical human monocyte subsets. Blood. 118:e16–31. DOI: 10.1182/blood-2010-12-326355. PMID: 21653326.

28. Jakubzick CV, Randolph GJ, Henson PM. 2017; Monocyte differentiation and antigen-presenting functions. Nat Rev Immunol. 17:349–62. DOI: 10.1038/nri.2017.28. PMID: 28436425.

29. Rőszer T. 2015; Understanding the mysterious M2 macrophage through activation markers and effector mechanisms. Mediators Inflamm. 2015:816460. DOI: 10.1155/2015/816460. PMID: 26089604. PMCID: PMC4452191.

30. Kapellos TS, Bonaguro L, Gemünd I, Reusch N, Saglam A, Hinkley ER, Schultze JL. 2019; Human monocyte subsets and phenotypes in major chronic inflammatory diseases. Front Immunol. 10:2035. DOI: 10.3389/fimmu.2019.02035. PMID: 31543877. PMCID: PMC6728754.

31. Tak T, van Groenendael R, Pickkers P, Koenderman L. 2017; Monocyte subsets are differentially lost from the circulation during acute inflammation induced by human experimental endotoxemia. J Innate Immun. 9:464–74. DOI: 10.1159/000475665. PMID: 28641299. PMCID: PMC6738874.

32. Askenase MH, Han SJ, Byrd AL, Morais da Fonseca D, Bouladoux N, Wilhelm C, Konkel JE, Hand TW, Lacerda-Queiroz N, Su XZ, Trinchieri G, Grainger JR, Belkaid Y. 2015; Bone-marrow-resident NK cells prime monocytes for regulatory function during infection. Immunity. 42:1130–42. DOI: 10.1016/j.immuni.2015.05.011. PMID: 26070484. PMCID: PMC4472558.