Research advance of Kupffer cells in liver diseases_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

XU Yang ,  MA Yong

Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin 150001, P. R. China;

Corresponding author：

MA Yong, Email: doctormy80@163.com

Keywords：

Kupffer cell; liver disease; new progress; review

DOI：

10.7507/1007-9424.202007090

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To summarize the relationship between Kupffer cells (KCs) and liver diseases.Methods The related literatures about the research progress of KCs in liver diseases in recent years were collected and analyzed.Results KCs were an important component of the monocyte-macrophage system. In a specific environment, activated KCs participated in a variety of inflammatory reactions, immune tolerance, and damage to hepatocytes by presenting antigens, secreting cytokines and chemokines, phagocytosis, and so on. KCs could not only be activated into M1 to promote inflammatory reaction and aggravate hepatocyte injury, but also could be activated to M2 to play an anti-inflammatory effect and improve liver injury. The role of KCs in liver diseases was very complex, but it also had potential research value.Conclusion KCs can affect the progression of liver diseases through many mechanisms and can provide new ideas for the prevention and treatment of liver diseases.

Citation： XU Yang, MA Yong. Research advance of Kupffer cells in liver diseases. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2021, 28(5): 673-677. doi: 10.7507/1007-9424.202007090 Copy

1.	Li P, He K, Li J, et al. The role of Kupffer cells in hepatic diseases. Mol Immunol, 2017, 85: 222-229.
2.	Tasnim F, Xing J, Huang X, et al. Generation of mature Kupffer cells from human induced pluripotent stem cells. Biomaterials, 2019, 192: 377-391.
3.	Manne V, Handa P, Kowdley KV. Pathophysiology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Clin Liver Dis, 2018, 22(1): 23-37.
4.	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. PLoS One, 2016, 11(7): e0159524.
5.	Wan J, Benkdane M, Teixeira-Clerc F, et al. M2 Kupffer cells promote M1 Kupffer cell apoptosis: a protective mechanism against alcoholic and nonalcoholic fatty liver disease. Hepatology, 2014, 59(1): 130-142.
6.	Li Z, Feng PP, Zhao ZB, et al. Liraglutide protects against inflammatory stress in non-alcoholic fatty liver by modulating Kupffer cells M2 polarization via cAMP-PKA-STAT3 signaling pathway. Biochem Biophys Res Commun, 2019, 510(1): 20-26.
7.	Wu H, Zhong Z, Wang A, et al. LncRNA FTX represses the progression of non-alcoholic fatty liver disease to hepatocellular carcinoma via regulating the M1/M2 polarization of Kupffer cells. Cancer Cell Int, 2020, 20: 266.
8.	Teschke R. Alcoholic liver disease: alcohol metabolism, cascade of molecular mechanisms, cellular targets, and clinical aspects. Biomedicines, 2018, 6(4): 106.
9.	Saikia P, Bellos D, McMullen MR, et al. MicroRNA 181b-3p and its target importin α5 regulate toll-like receptor 4 signaling in Kupffer cells and liver injury in mice in response to ethanol. Hepatology, 2017, 66(2): 602-615.
10.	Luo P, Wang F, Wong NK, et al. Divergent roles of Kupffer cell TLR2/3 signaling in alcoholic liver disease and the protective role of EGCG. Cell Mol Gastroenterol Hepatol, 2020, 9(1): 145-160.
11.	Wu G, Yang Q, Yu Y, et al. Taurine inhibits Kupffer cells activation induced by lipopolysaccharide in alcoholic liver damaged rats. Adv Exp Med Biol, 2017, 975 Pt 2: 789-800.
12.	Park JK, Shao M, Kim MY, et al. An endoplasmic reticulum protein, Nogo-B, facilitates alcoholic liver disease through regulation of Kupffer cell polarization. Hepatology, 2017, 65(5): 1720-1734.
13.	Koyama Y, Brenner DA. Liver inflammation and fibrosis. J Clin Invest, 2017, 127(1): 55-64.
14.	Kim J, Bang H, Ahn M, et al. Allyl isothiocyanate reduces liver fibrosis by regulating Kupffer cell activation in rats. J Vet Med Sci, 2018, 80(6): 893-897.
15.	Zhao XA, Chen G, Liu Y, et al. Curcumin reduces Ly6C^hi monocyte infiltration to protect against liver fibrosis by inhibiting Kupffer cells activation to reduce chemokines secretion. Biomed Pharmacother, 2018, 106: 868-878.
16.	Takemura S, Azuma H, Osada-Oka M, et al. S-allyl-glutathione improves experimental liver fibrosis by regulating Kupffer cell activation in rats. Am J Physiol Gastrointest Liver Physiol, 2018, 314(2): G150-G163.
17.	Bartneck M, Scheyda KM, Warzecha KT, et al. Fluorescent cell-traceable dexamethasone-loaded liposomes for the treatment of inflammatory liver diseases. Biomaterials, 2015, 37: 367-382.
18.	Wu Y, Zhang W, Li M, et al. Nobiletin ameliorates ischemia-reperfusion injury by suppressing the function of Kupffer cells after liver transplantation in rats. Biomed Pharmacother, 2017, 89: 732-741.
19.	Banan B, Xiao Z, Watson R, et al. Novel strategy to decrease reperfusion injuries and improve function of cold-preserved livers using normothermic ex vivo liver perfusion machine. Liver Transpl, 2016, 22(3): 333-343.
20.	Xu X, Wang M, Li JZ, et al. Tauroursodeoxycholic acid alleviates hepatic ischemia reperfusion injury by suppressing the function of Kupffer cells in mice. Biomed Pharmacother, 2018, 106: 1271-1281.
21.	Li X, Wang J, Song X, et al. Ketamine ameliorates ischemia-reperfusion injury after liver autotransplantation by suppressing activation of Kupffer cells in rats. Can J Physiol Pharmacol, 2018, 96(9): 886-892.
22.	Al-Saeedi M, Liang R, Schultze DP, et al. Glycine protects partial liver grafts from Kupffer cell-dependent ischemia-reperfusion injury without negative effect on regeneration. Amino Acids, 2019, 51(6): 903-911.
23.	Li Y, Ma D, Wang Z, et al. MicroRNA-155 deficiency in Kupffer cells ameliorates liver ischemia-reperfusion injury in mice. Transplantation, 2017, 101(7): 1600-1608.
24.	Yang F, Wang S, Liu Y, et al. IRE1α aggravates ischemia reperfusion injury of fatty liver by regulating phenotypic transformation of Kupffer cells. Free Radic Biol Med, 2018, 124: 395-407.
25.	Martínez-Cardona C, Lozano-Ruiz B, Bachiller V, et al. AIM2 deficiency reduces the development of hepatocellular carcinoma in mice. Int J Cancer, 2018, 143(11): 2997-3007.
26.	Li XY, Wu L, Li SW, et al. Effect of CD16a, the surface receptor of Kupffer cells, on the growth of hepatocellular carcinoma cells. Int J Mol Med, 2016, 37(6): 1465-1474.
27.	Li M, Lai X, Zhao Y, et al. Loss of NDRG2 in liver microenvironment inhibits cancer liver metastasis by regulating tumor associate macrophages polarization. Cell Death Dis, 2018, 9(2): 248.
28.	Wang B, Li X, Hu W, et al. Silencing of lncRNA SNHG20 delays the progression of nonalcoholic fatty liver disease to hepatocellular carcinoma via regulating liver Kupffer cells polarization. IUBMB Life, 2019, 71(12): 1952-1961.
29.	Yuan F, Zhang W, Mu D, et al. Kupffer cells in immune activation and tolerance toward HBV/HCV infection. Adv Clin Exp Med, 2017, 26(4): 739-745.
30.	Wang W, Bian H, Li F, et al. HBeAg induces the expression of macrophage miR-155 to accelerate liver injury via promoting production of inflammatory cytokines. Cell Mol Life Sci, 2018, 75(14): 2627-2641.
31.	Golden-Mason L, Rosen HR. Galectin-9: Diverse roles in hepatic immune homeostasis and inflammation. Hepatology, 2017, 66(1): 271-279.
32.	Wu LL, Peng WH, Wu HL, et al. Lymphocyte antigen 6 complex, locus C⁺ monocytes and Kupffer cells orchestrate liver immune responses against hepatitis B virus in mice. Hepatology, 2019, 69(6): 2364-2380.
33.	Liu XQ, Wei RR, Wang CC, et al. Relationship between PK2 and number of Kupffer cells during the progression of liver fibrosis in patients with HBV. Turk J Med Sci, 2018, 48(1): 52-61.
34.	Borst K, Frenz T, Spanier J, et al. Type Ⅰ interferon receptor signaling delays Kupffer cell replenishment during acute fulminant viral hepatitis. J Hepatol, 2018, 68(4): 682-690.
35.	Lotowska JM, Sobaniec-Lotowska ME, Daniluk U, et al. Glassy droplet inclusions within the cytoplasm of Kupffer cells: a novel ultrastructural feature for the diagnosis of pediatric autoimmune hepatitis. Dig Liver Dis, 2017, 49(8): 929-933.
36.	Kegel V, Pfeiffer E, Burkhardt B, et al. Subtoxic concentrations of hepatotoxic drugs lead to Kupffer cell activation in a human in vitro liver model: an approach to study DILI. Mediators Inflamm, 2015, 2015: 640631.
37.	Sato K, Hall C, Glaser S, et al. Pathogenesis of Kupffer cells in cholestatic liver injury. Am J Pathol, 2016, 186(9): 2238-2247.

1. Li P, He K, Li J, et al. The role of Kupffer cells in hepatic diseases. Mol Immunol, 2017, 85: 222-229.
2. Tasnim F, Xing J, Huang X, et al. Generation of mature Kupffer cells from human induced pluripotent stem cells. Biomaterials, 2019, 192: 377-391.
3. Manne V, Handa P, Kowdley KV. Pathophysiology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Clin Liver Dis, 2018, 22(1): 23-37.
4. 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. PLoS One, 2016, 11(7): e0159524.
5. Wan J, Benkdane M, Teixeira-Clerc F, et al. M2 Kupffer cells promote M1 Kupffer cell apoptosis: a protective mechanism against alcoholic and nonalcoholic fatty liver disease. Hepatology, 2014, 59(1): 130-142.
6. Li Z, Feng PP, Zhao ZB, et al. Liraglutide protects against inflammatory stress in non-alcoholic fatty liver by modulating Kupffer cells M2 polarization via cAMP-PKA-STAT3 signaling pathway. Biochem Biophys Res Commun, 2019, 510(1): 20-26.
7. Wu H, Zhong Z, Wang A, et al. LncRNA FTX represses the progression of non-alcoholic fatty liver disease to hepatocellular carcinoma via regulating the M1/M2 polarization of Kupffer cells. Cancer Cell Int, 2020, 20: 266.
8. Teschke R. Alcoholic liver disease: alcohol metabolism, cascade of molecular mechanisms, cellular targets, and clinical aspects. Biomedicines, 2018, 6(4): 106.
9. Saikia P, Bellos D, McMullen MR, et al. MicroRNA 181b-3p and its target importin α5 regulate toll-like receptor 4 signaling in Kupffer cells and liver injury in mice in response to ethanol. Hepatology, 2017, 66(2): 602-615.
10. Luo P, Wang F, Wong NK, et al. Divergent roles of Kupffer cell TLR2/3 signaling in alcoholic liver disease and the protective role of EGCG. Cell Mol Gastroenterol Hepatol, 2020, 9(1): 145-160.
11. Wu G, Yang Q, Yu Y, et al. Taurine inhibits Kupffer cells activation induced by lipopolysaccharide in alcoholic liver damaged rats. Adv Exp Med Biol, 2017, 975 Pt 2: 789-800.
12. Park JK, Shao M, Kim MY, et al. An endoplasmic reticulum protein, Nogo-B, facilitates alcoholic liver disease through regulation of Kupffer cell polarization. Hepatology, 2017, 65(5): 1720-1734.
13. Koyama Y, Brenner DA. Liver inflammation and fibrosis. J Clin Invest, 2017, 127(1): 55-64.
14. Kim J, Bang H, Ahn M, et al. Allyl isothiocyanate reduces liver fibrosis by regulating Kupffer cell activation in rats. J Vet Med Sci, 2018, 80(6): 893-897.
15. Zhao XA, Chen G, Liu Y, et al. Curcumin reduces Ly6C^hi monocyte infiltration to protect against liver fibrosis by inhibiting Kupffer cells activation to reduce chemokines secretion. Biomed Pharmacother, 2018, 106: 868-878.
16. Takemura S, Azuma H, Osada-Oka M, et al. S-allyl-glutathione improves experimental liver fibrosis by regulating Kupffer cell activation in rats. Am J Physiol Gastrointest Liver Physiol, 2018, 314(2): G150-G163.
17. Bartneck M, Scheyda KM, Warzecha KT, et al. Fluorescent cell-traceable dexamethasone-loaded liposomes for the treatment of inflammatory liver diseases. Biomaterials, 2015, 37: 367-382.
18. Wu Y, Zhang W, Li M, et al. Nobiletin ameliorates ischemia-reperfusion injury by suppressing the function of Kupffer cells after liver transplantation in rats. Biomed Pharmacother, 2017, 89: 732-741.
19. Banan B, Xiao Z, Watson R, et al. Novel strategy to decrease reperfusion injuries and improve function of cold-preserved livers using normothermic ex vivo liver perfusion machine. Liver Transpl, 2016, 22(3): 333-343.
20. Xu X, Wang M, Li JZ, et al. Tauroursodeoxycholic acid alleviates hepatic ischemia reperfusion injury by suppressing the function of Kupffer cells in mice. Biomed Pharmacother, 2018, 106: 1271-1281.
21. Li X, Wang J, Song X, et al. Ketamine ameliorates ischemia-reperfusion injury after liver autotransplantation by suppressing activation of Kupffer cells in rats. Can J Physiol Pharmacol, 2018, 96(9): 886-892.
22. Al-Saeedi M, Liang R, Schultze DP, et al. Glycine protects partial liver grafts from Kupffer cell-dependent ischemia-reperfusion injury without negative effect on regeneration. Amino Acids, 2019, 51(6): 903-911.
23. Li Y, Ma D, Wang Z, et al. MicroRNA-155 deficiency in Kupffer cells ameliorates liver ischemia-reperfusion injury in mice. Transplantation, 2017, 101(7): 1600-1608.
24. Yang F, Wang S, Liu Y, et al. IRE1α aggravates ischemia reperfusion injury of fatty liver by regulating phenotypic transformation of Kupffer cells. Free Radic Biol Med, 2018, 124: 395-407.
25. Martínez-Cardona C, Lozano-Ruiz B, Bachiller V, et al. AIM2 deficiency reduces the development of hepatocellular carcinoma in mice. Int J Cancer, 2018, 143(11): 2997-3007.
26. Li XY, Wu L, Li SW, et al. Effect of CD16a, the surface receptor of Kupffer cells, on the growth of hepatocellular carcinoma cells. Int J Mol Med, 2016, 37(6): 1465-1474.
27. Li M, Lai X, Zhao Y, et al. Loss of NDRG2 in liver microenvironment inhibits cancer liver metastasis by regulating tumor associate macrophages polarization. Cell Death Dis, 2018, 9(2): 248.
28. Wang B, Li X, Hu W, et al. Silencing of lncRNA SNHG20 delays the progression of nonalcoholic fatty liver disease to hepatocellular carcinoma via regulating liver Kupffer cells polarization. IUBMB Life, 2019, 71(12): 1952-1961.
29. Yuan F, Zhang W, Mu D, et al. Kupffer cells in immune activation and tolerance toward HBV/HCV infection. Adv Clin Exp Med, 2017, 26(4): 739-745.
30. Wang W, Bian H, Li F, et al. HBeAg induces the expression of macrophage miR-155 to accelerate liver injury via promoting production of inflammatory cytokines. Cell Mol Life Sci, 2018, 75(14): 2627-2641.
31. Golden-Mason L, Rosen HR. Galectin-9: Diverse roles in hepatic immune homeostasis and inflammation. Hepatology, 2017, 66(1): 271-279.
32. Wu LL, Peng WH, Wu HL, et al. Lymphocyte antigen 6 complex, locus C⁺ monocytes and Kupffer cells orchestrate liver immune responses against hepatitis B virus in mice. Hepatology, 2019, 69(6): 2364-2380.
33. Liu XQ, Wei RR, Wang CC, et al. Relationship between PK2 and number of Kupffer cells during the progression of liver fibrosis in patients with HBV. Turk J Med Sci, 2018, 48(1): 52-61.
34. Borst K, Frenz T, Spanier J, et al. Type Ⅰ interferon receptor signaling delays Kupffer cell replenishment during acute fulminant viral hepatitis. J Hepatol, 2018, 68(4): 682-690.
35. Lotowska JM, Sobaniec-Lotowska ME, Daniluk U, et al. Glassy droplet inclusions within the cytoplasm of Kupffer cells: a novel ultrastructural feature for the diagnosis of pediatric autoimmune hepatitis. Dig Liver Dis, 2017, 49(8): 929-933.
36. Kegel V, Pfeiffer E, Burkhardt B, et al. Subtoxic concentrations of hepatotoxic drugs lead to Kupffer cell activation in a human in vitro liver model: an approach to study DILI. Mediators Inflamm, 2015, 2015: 640631.
37. Sato K, Hall C, Glaser S, et al. Pathogenesis of Kupffer cells in cholestatic liver injury. Am J Pathol, 2016, 186(9): 2238-2247.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Research advance of Kupffer cells in liver diseases

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