Letter to the editor

Kupffer cells in hepatotoxicity

Reham Hassan1[*]

1Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt

EXCLI J 2020;19:Doc1156


Dear Editor,

Recently, Gao and colleagues published a study about the role of Kupffer cells in hepatotoxicity (Gao et al., 2020[1]). The authors used a damage model with combined flucloxacillin and CpG-oligodeoxynucleotides in mice. Flucloxacillin is used for the treatment of Gram-negative infections and is known to induce liver damage in a small fraction of patients (Russmann et al., 2005[10]). To recapitulate flucloxacillin induced hepatotoxicity in mice, the antibiotic has been co-administered with CpG-oligodeoxynucleotides, because the latter initiate innate immune responses (Takeshita et al., 2001[13]; Hemmi et al., 2000[3]; Gao et al., 2020[1]). The combination flucloxacillin plus CpG-oligodeoxynucleotides mediates Fas ligand dependent apoptosis of hepatocytes via natural killer cells (Gao et al., 2020[1]; Song et al., 2019[12]).

In their present study, Gao et al. removed Kupffer cells by treatment of the mice with GdCl3 (Gao et al., 2020[1]). Interestingly, the authors observed that GdCl3 treated mice showed less liver damage compared to mice that received flucloxacillin plus CpG-oligodeoxynucleotides only. This result suggests that Kupffer cells activate natural killer cells that subsequently induce apoptosis of hepatocytes in this mouse model.

Kupffer cells are known as important modifiers of hepatotoxicity (Kessler et al., 2014[5]; Reif et al., 2017[9]; Pfeiffer et al., 2015[8]). They filter bacterial fragments and particles out of the sinusoidal blood (Godoy et al., 2013[2]; Köppert et al., 2018[6]) but by the release of cytokines may also contribute to the aggravation of liver damage (Tsutsui and Nishiguchi, 2014[14]; Hou et al., 2017[4]; Leist et al., 2017[7]; Schenk et al., 2017[11]). The present study of Gao and colleagues contributes an important piece of information how hepatotoxic compounds and modifiers of immune cell functions may interact to cause liver damage.

Conflict of interest

The authors declare no conflict of interest.



1. Gao Y, Song B, Aoki S, Kousei Ito K. Role of Kupffer cells in liver injury induced by CpG oligodeoxynucleotide and flucloxacillin in mice. EXCLI J. 2020;19:387-99. doi: 10.17179/excli2020-1103
2. Godoy P, Hewitt NJ, Albrecht U, Andersen ME, Ansari N, Bhattacharya S, et al. Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME. Arch Toxicol. 2013;87:1315-530. doi: 10.1007/s00204-013-1078-5
3. Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, et al. A Toll-like receptor recognizes bacterial DNA. Nature. 2000;408(6813):740–5. doi: 10.1038/35047123
4. Hou X, Hao XL, Zheng MJ, Xu CF, Wang J, Zhou RB, et al. CD205-TLR9-IL-12 axis contributes to CpG-induced oversensitive liver injury in HBsAg transgenic mice by promoting the interaction of NKT cells with Kupffer cells. Cell Mol Immunol. 2017;14:675–84. doi: 10.1038/cmi.2015.111
5. Kessler SM, Simon Y, Gemperlein K, Gianmoena K, Cadenas C, Zimmer V, et al. Fatty acid elongation in non-alcoholic steatohepatitis and hepatocellular carcinoma. Int J Mol Sci. 2014;15:5762-73. doi: 10.3390/ijms15045762
6. Köppert S, Büscher A, Babler A, Ghallab A, Buhl EM, Latz E, et al. Cellular clearance and biological activity of calciprotein particles depend on their maturation state and crystallinity. Front Immunol. 2018;9:1991. doi: 10.3389/fimmu.2018.01991
7. Leist M, Ghallab A, Graepel R, Marchan R, Hassan R, Bennekou SH, et al. Adverse outcome pathways: opportunities, limitations and open questions. Arch Toxicol. 2017;91:3477-505. doi: 10.1007/s00204-017-2045-3
8. Pfeiffer E, Kegel V, Zeilinger K, Hengstler JG, Nüssler AK, Seehofer D, et al. Featured article: Isolation, characterization, and cultivation of human hepatocytes and non-parenchymal liver cells. Exp Biol Med (Maywood). 2015;240:645-56. doi: 10.1177/1535370214558025
9. Reif R, Ghallab A, Beattie L, Günther G, Kuepfer L, Kaye PM, et al. In vivo imaging of systemic transport and elimination of xenobiotics and endogenous molecules in mice. Arch Toxicol. 2017;91:1335-52. doi: 10.1007/s00204-016-1906-5
10. Russmann S, Kaye JA, Jick SS, Jick H. Risk of cholestatic liver disease associated with flucloxacillin and flucloxacillin prescribing habits in the UK: Cohort study using data from the UK General Practice Research Database. Brit J Clin Pharmacol. 2005;60:76–82. doi: 10.1111/j.1365-2125.2005.02370.x
11. Schenk A, Ghallab A, Hofmann U, Hassan R, Schwarz M, Schuppert A, et al. Physiologically-based modelling in mice suggests an aggravated loss of clearance capacity after toxic liver damage. Sci Rep. 2017;7:6224. doi: 10.1038/s41598-017-04574-z
12. Song BB, Aoki S, Liu C, Ito K. A toll-like receptor 9 agonist sensitizes mice to mitochondrial dysfunction-induced hepatic apoptosis via the Fas/FasL pathway. Arch Toxicol. 2019;93:1573–84. doi: 10.1007/s00204-019-02454-1
13. Takeshita F, Leifer CA, Gursel I, Ishii KJ, Takeshita S, Gursel M, et al. Cutting edge: Role of toll-like receptor 9 in CpG DNA-induced activation of human cells. J Immunol. 2001;167:3555–8. doi: 10.4049/jimmunol.167.7.3555
14. Tsutsui H, Nishiguchi S. Importance of Kupffer cells in the development of acute liver injuries in mice. Int J Mol Sci. 2014;15:7711–30. doi: 10.3390/ijms15057711

[*] Corresponding Author:

Reham Hassan, Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt, eMail: reham_hassan@vet.svu.edu.eg