UNLABELLED: Liver fibrosis is a common scarring response to all forms of chronic liver injury and is always associated with inflammation that contributes to fibrogenesis. Although a variety of cell populations infiltrate the liver during inflammation, it is generically clear that CD8 T lymphocytes promote while natural killer (NK) cells inhibit liver fibrosis. However, the role of invariant natural killer T (iNKT) cells, which are abundant in the liver, in hepatic fibrogenesis, remains obscure. Here we show that iNKT-deficient mice are more susceptible to carbon tetrachloride (CCl(4))-induced acute liver injury and inflammation. The protective effect of naturally activated iNKT in this model is likely mediated via suppression of the proinflammatory effect of activated hepatic stellate cells. Interestingly, strong activation of iNKT through injection of iNKT activator alpha-galactosylceramide (alpha-GalCer) accelerates CCl(4)-induced acute liver injury and fibrosis. In contrast, chronic CCl(4) administration induces a similar degree of liver injury in iNKT-deficient and wild-type mice, and only a slightly higher grade of liver fibrosis in iNKT-deficient mice than wild-type mice 2 weeks but not 4 weeks after CCl(4) injection, although iNKT cells are able to kill activated stellate cells. An insignificant role of iNKT in chronic liver injury and fibrosis may be attributable to hepatic iNKT cell depletion. Finally, chronic alpha-GalCer treatment had little effect on liver injury and fibrosis, which is attributable to iNKT tolerance after alpha-GalCer injection. CONCLUSION: Natural activation of hepatic iNKT cells inhibits, whereas strong activation of iNKT cells by alpha-GalCer accelerates CCl(4)-induced acute liver injury, inflammation, and fibrosis. During chronic liver injury, hepatic iNKT cells are depleted and play a role in inhibiting liver fibrosis in the early stage but not the late stage of fibrosis.
UNLABELLED: Liver fibrosis is a common scarring response to all forms of chronic liver injury and is always associated with inflammation that contributes to fibrogenesis. Although a variety of cell populations infiltrate the liver during inflammation, it is generically clear that CD8 T lymphocytes promote while natural killer (NK) cells inhibit liver fibrosis. However, the role of invariant natural killer T (iNKT) cells, which are abundant in the liver, in hepatic fibrogenesis, remains obscure. Here we show that iNKT-deficient mice are more susceptible to carbon tetrachloride (CCl(4))-induced acute liver injury and inflammation. The protective effect of naturally activated iNKT in this model is likely mediated via suppression of the proinflammatory effect of activated hepatic stellate cells. Interestingly, strong activation of iNKT through injection of iNKT activator alpha-galactosylceramide (alpha-GalCer) accelerates CCl(4)-induced acute liver injury and fibrosis. In contrast, chronic CCl(4) administration induces a similar degree of liver injury in iNKT-deficient and wild-type mice, and only a slightly higher grade of liver fibrosis in iNKT-deficient mice than wild-type mice 2 weeks but not 4 weeks after CCl(4) injection, although iNKT cells are able to kill activated stellate cells. An insignificant role of iNKT in chronic liver injury and fibrosis may be attributable to hepatic iNKT cell depletion. Finally, chronic alpha-GalCer treatment had little effect on liver injury and fibrosis, which is attributable to iNKT tolerance after alpha-GalCer injection. CONCLUSION: Natural activation of hepatic iNKT cells inhibits, whereas strong activation of iNKT cells by alpha-GalCer accelerates CCl(4)-induced acute liver injury, inflammation, and fibrosis. During chronic liver injury, hepatic iNKT cells are depleted and play a role in inhibiting liver fibrosis in the early stage but not the late stage of fibrosis.
Authors: Ya-Hui Chuang; Zhe-Xiong Lian; Guo-Xiang Yang; Shang-An Shu; Yuki Moritoki; William M Ridgway; Aftab A Ansari; Mitchell Kronenberg; Richard A Flavell; Bin Gao; M Eric Gershwin Journal: Hepatology Date: 2008-02 Impact factor: 17.425
Authors: Alisan Kahraman; Fernando J Barreyro; Steven F Bronk; Nathan W Werneburg; Justin L Mott; Yuko Akazawa; Howard C Masuoka; Charles L Howe; Gregory J Gores Journal: Hepatology Date: 2008-04 Impact factor: 17.425
Authors: Mark A Barnes; Megan R McMullen; Sanjoy Roychowdhury; Nabil Z Madhun; Kathryn Niese; Mitchell A Olman; Abram B Stavitsky; Richard Bucala; Laura E Nagy Journal: J Leukoc Biol Date: 2014-11-14 Impact factor: 4.962
Authors: Denitra A Breuer; Maria Cristina Pacheco; M Kay Washington; Stephanie A Montgomery; Alyssa H Hasty; Arion J Kennedy Journal: Am J Physiol Gastrointest Liver Physiol Date: 2019-11-11 Impact factor: 4.052