NKT cells in liver fibrosis: Controversies or complexities
Authors: Hua Wang, Ogyi Park, Bin Gao
Journal: Journal of Hepatology (2011)

CD1d-restricted natural killer T cells contribute to hepatic inflammation and fibrogenesis in miceJournal of HepatologyVol. 54Issue 6PreviewSeveral lines of evidence suggest that innate immunity plays a key role in hepatic fibrogenesis. To clarify the role of natural killer (NK) T cells in hepatic inflammation and fibrogenesis, we here investigated xenobiotics-induced liver injury and subsequent fibrogenesis in mice lacking mature NKT cells caused by genetic disruption of the CD1d molecule. Full-Text PDF Reply to: "NKT cells in liver fibrosis: Controversies or complexities"Journal of HepatologyVol. 55Issue 5PreviewEmerging attention has been paid to the role of natural killer T (NKT) cells in a variety of liver diseases including nonalcoholic steatohepatitis (NASH) [1]. The role of NKT cells in hepatic fibrogenesis, however, has been controversial [2–4]. In our latest manuscript entitled "CD1d-restricted natural killer T cells contribute to hepatic inflammation and fibrogenesis in mice", we demonstrated that CD1d-restricted natural killer (NK) T cells play an exacerbating role in xenobiotics-induced liver injury and subsequent fibrogenesis using CD1d-knockout (KO) mice [5]. Full-Text PDF Open Access We read with great interest a recent article in the Journal of Hepatology by Ishikawa et al. investigating the role of CD1d-restricted natural killer T (NKT) cells in thioacetamide (TAA)-induced liver fibrosis, by using CD1d knockout (KO) mice that are associated with NKT cell deficiency [[1]Ishikawa S. Ikejima K. Yamagata H. Aoyama T. Kon K. Arai K. et al.CD1d-restricted natural killer T cells contribute to hepatic inflammation and fibrogenesis in mice.J Hepatol. 2011; 54: 1195-1204Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar]. First, the authors observed that CD1d KO mice were resistant to TAA-induced liver inflammation, damage, and hepatocyte apoptosis. Second, the authors observed CD1d KO mice were resistant to TAA-induced liver fibrosis, indicating that NKT cells play an important role in promoting liver fibrogenesis in mice after chronic TAA treatment. The pro-fibrotic effects of NKT cells were also recently suggested by the data from a murine model of HBV transgenic mice [[2]Jin Z. Sun R. Wei H. Gao X. Chen Y. Tian Z. Accelerated liver fibrosis in hepatitis B virus transgenic mice: involvement of natural killer T cells.Hepatology. 2011; 53: 219-229Crossref PubMed Scopus (80) Google Scholar], primary biliary cirrhosis [[3]Wu S.J. Yang Y.H. Tsuneyama K. Leung P.S. Illarionov P. Gershwin M.E. et al.Innate immunity and primary biliary cirrhosis: activated invariant natural killer T cells exacerbate murine autoimmune cholangitis and fibrosis.Hepatology. 2011; 53: 915-925Crossref PubMed Scopus (80) Google Scholar], nonalcoholic steatohepatitis (NASH), and patients with NASH [[4]Syn WK, Oo YH, Pereira TA, Karaca GF, Jung Y, Omenetti A, et al. Accumulation of natural killer T cells in progressive nonalcoholic fatty liver disease. Hepatology (Baltimore, Md) 2010;51:1998–2007.Google Scholar].Recently, we identified the double sword face of invariant NKT (iNKT, type I NKT) cells in liver fibrogenesis in a model of CCl4-induced liver injury [[5]Park O, Jeong WI, Wang L, Wang H, Lian ZX, Gershwin ME, et al. Diverse roles of invariant natural killer T cells in liver injury and fibrosis induced by carbon tetrachloride. Hepatology (Baltimore, Md) 2009;49:1683–1694.Google Scholar]. On the one hand, iNKT-deficient mice had increased liver injury and fibrosis, especially in the early stage of CCl4-induced liver injury, suggesting that natural activation of iNKT cells by endogenous lipid antigens plays a protective role in preventing CCl4-induced liver injury and fibrosis. On the other hand, strong activation of iNKT cells by α-galactosylceramide (α-GalCer) accelerated CCl4-induced hepatocellular injury and subsequently enhanced fibrosis. Our findings clearly suggest a complex role of iNKT cells in liver fibrosis: inhibiting liver fibrosis via the suppression of HSC activation or indirectly promoting liver fibrosis via enhancing liver injury. We believe that the final effect of iNKT cells on liver fibrosis is determined by the balance between the inhibitory and stimulatory effects as we discussed above, but may also dependent on the real context of developing stage human liver diseases or animal models used. In addition to iNKT (type I NKT) cells, other subtypes of NKT cells including type II and possible type III NKT cells also exist [[6]Gao B. Radaeva S. Park O. Liver natural killer and natural killer T cells: immunobiology and emerging roles in liver diseases.J Leuk Biol. 2009; 86: 513-528Crossref PubMed Google Scholar]. These different subtypes of NKT cells exert many similar functions but may also exert some opposing functions, which further complicates the role of NKT cells in liver fibrogenesis [6Gao B. Radaeva S. Park O. Liver natural killer and natural killer T cells: immunobiology and emerging roles in liver diseases.J Leuk Biol. 2009; 86: 513-528Crossref PubMed Google Scholar, 7Notas G. Kisseleva T. Brenner D. NK and NKT cells in liver injury and fibrosis.Clin Immunol. 2009; 130: 16-26Crossref PubMed Scopus (105) Google Scholar].In the study by Ishikawa et al. [[1]Ishikawa S. Ikejima K. Yamagata H. Aoyama T. Kon K. Arai K. et al.CD1d-restricted natural killer T cells contribute to hepatic inflammation and fibrogenesis in mice.J Hepatol. 2011; 54: 1195-1204Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar], it appears that CD1d restricted NKT cells play an important role in inducing liver injury, which may contribute to the pro-fibrotic effects of NKT cells observed in the TAA-induced liver injury model. In the Supplementary material, Ishikawa et al. [[1]Ishikawa S. Ikejima K. Yamagata H. Aoyama T. Kon K. Arai K. et al.CD1d-restricted natural killer T cells contribute to hepatic inflammation and fibrogenesis in mice.J Hepatol. 2011; 54: 1195-1204Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar], reported that CD1d KO mice were also resistant to CCl4-induced acute liver injury; however, we found that CD1d KO mice had similar liver injury and fibrosis after chronic treatment with CCl4 (Park et al., unpublished data). Further studies are required to clarify the complex role of NKT cells in liver injury and fibrosis.Conflict of interestThe underlying research reported in the study was funded by the NIH Institutes of Health. We read with great interest a recent article in the Journal of Hepatology by Ishikawa et al. investigating the role of CD1d-restricted natural killer T (NKT) cells in thioacetamide (TAA)-induced liver fibrosis, by using CD1d knockout (KO) mice that are associated with NKT cell deficiency [[1]Ishikawa S. Ikejima K. Yamagata H. Aoyama T. Kon K. Arai K. et al.CD1d-restricted natural killer T cells contribute to hepatic inflammation and fibrogenesis in mice.J Hepatol. 2011; 54: 1195-1204Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar]. First, the authors observed that CD1d KO mice were resistant to TAA-induced liver inflammation, damage, and hepatocyte apoptosis. Second, the authors observed CD1d KO mice were resistant to TAA-induced liver fibrosis, indicating that NKT cells play an important role in promoting liver fibrogenesis in mice after chronic TAA treatment. The pro-fibrotic effects of NKT cells were also recently suggested by the data from a murine model of HBV transgenic mice [[2]Jin Z. Sun R. Wei H. Gao X. Chen Y. Tian Z. Accelerated liver fibrosis in hepatitis B virus transgenic mice: involvement of natural killer T cells.Hepatology. 2011; 53: 219-229Crossref PubMed Scopus (80) Google Scholar], primary biliary cirrhosis [[3]Wu S.J. Yang Y.H. Tsuneyama K. Leung P.S. Illarionov P. Gershwin M.E. et al.Innate immunity and primary biliary cirrhosis: activated invariant natural killer T cells exacerbate murine autoimmune cholangitis and fibrosis.Hepatology. 2011; 53: 915-925Crossref PubMed Scopus (80) Google Scholar], nonalcoholic steatohepatitis (NASH), and patients with NASH [[4]Syn WK, Oo YH, Pereira TA, Karaca GF, Jung Y, Omenetti A, et al. Accumulation of natural killer T cells in progressive nonalcoholic fatty liver disease. Hepatology (Baltimore, Md) 2010;51:1998–2007.Google Scholar]. Recently, we identified the double sword face of invariant NKT (iNKT, type I NKT) cells in liver fibrogenesis in a model of CCl4-induced liver injury [[5]Park O, Jeong WI, Wang L, Wang H, Lian ZX, Gershwin ME, et al. Diverse roles of invariant natural killer T cells in liver injury and fibrosis induced by carbon tetrachloride. Hepatology (Baltimore, Md) 2009;49:1683–1694.Google Scholar]. On the one hand, iNKT-deficient mice had increased liver injury and fibrosis, especially in the early stage of CCl4-induced liver injury, suggesting that natural activation of iNKT cells by endogenous lipid antigens plays a protective role in preventing CCl4-induced liver injury and fibrosis. On the other hand, strong activation of iNKT cells by α-galactosylceramide (α-GalCer) accelerated CCl4-induced hepatocellular injury and subsequently enhanced fibrosis. Our findings clearly suggest a complex role of iNKT cells in liver fibrosis: inhibiting liver fibrosis via the suppression of HSC activation or indirectly promoting liver fibrosis via enhancing liver injury. We believe that the final effect of iNKT cells on liver fibrosis is determined by the balance between the inhibitory and stimulatory effects as we discussed above, but may also dependent on the real context of developing stage human liver diseases or animal models used. In addition to iNKT (type I NKT) cells, other subtypes of NKT cells including type II and possible type III NKT cells also exist [[6]Gao B. Radaeva S. Park O. Liver natural killer and natural killer T cells: immunobiology and emerging roles in liver diseases.J Leuk Biol. 2009; 86: 513-528Crossref PubMed Google Scholar]. These different subtypes of NKT cells exert many similar functions but may also exert some opposing functions, which further complicates the role of NKT cells in liver fibrogenesis [6Gao B. Radaeva S. Park O. Liver natural killer and natural killer T cells: immunobiology and emerging roles in liver diseases.J Leuk Biol. 2009; 86: 513-528Crossref PubMed Google Scholar, 7Notas G. Kisseleva T. Brenner D. NK and NKT cells in liver injury and fibrosis.Clin Immunol. 2009; 130: 16-26Crossref PubMed Scopus (105) Google Scholar]. In the study by Ishikawa et al. [[1]Ishikawa S. Ikejima K. Yamagata H. Aoyama T. Kon K. Arai K. et al.CD1d-restricted natural killer T cells contribute to hepatic inflammation and fibrogenesis in mice.J Hepatol. 2011; 54: 1195-1204Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar], it appears that CD1d restricted NKT cells play an important role in inducing liver injury, which may contribute to the pro-fibrotic effects of NKT cells observed in the TAA-induced liver injury model. In the Supplementary material, Ishikawa et al. [[1]Ishikawa S. Ikejima K. Yamagata H. Aoyama T. Kon K. Arai K. et al.CD1d-restricted natural killer T cells contribute to hepatic inflammation and fibrogenesis in mice.J Hepatol. 2011; 54: 1195-1204Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar], reported that CD1d KO mice were also resistant to CCl4-induced acute liver injury; however, we found that CD1d KO mice had similar liver injury and fibrosis after chronic treatment with CCl4 (Park et al., unpublished data). Further studies are required to clarify the complex role of NKT cells in liver injury and fibrosis. Conflict of interestThe underlying research reported in the study was funded by the NIH Institutes of Health. The underlying research reported in the study was funded by the NIH Institutes of Health.