Diverse roles of invariant natural killer T cells in liver injury and fibrosis induced by carbon tetrachloride

Ogyi Park, Won Il Jeong, Lei Wang, Hua Wang, Zhe Xiong Lian, M. Eric Gershwin, Bin Gao

Research output: Contribution to journalArticle

Abstract

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 (CCl4)-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 α-galactosylceramide (α-GalCer) accelerates CCl4-induced acute liver injury and fibrosis. In contrast, chronic CCl4 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 CCl4 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 α-GalCer treatment had little effect on liver injury and fibrosis, which is attributable to iNKT tolerance after α-GalCer injection. Conclusion: Natural activation of hepatic iNKT cells inhibits, whereas strong activation of iNKT cells by α-GalCer accelerates CCl4-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.

Original languageEnglish (US)
Pages (from-to)1683-1694
Number of pages12
JournalHepatology
Volume49
Issue number5
DOIs
StatePublished - May 2009
Externally publishedYes

Fingerprint

Natural Killer T-Cells
Carbon Tetrachloride
Liver Cirrhosis
Liver
Wounds and Injuries
Inflammation
Injections
Fibrosis
Galactosylceramides
Hepatic Stellate Cells
Natural Killer Cells
Cicatrix

ASJC Scopus subject areas

  • Hepatology
  • Medicine(all)

Cite this

Park, O., Jeong, W. I., Wang, L., Wang, H., Lian, Z. X., Gershwin, M. E., & Gao, B. (2009). Diverse roles of invariant natural killer T cells in liver injury and fibrosis induced by carbon tetrachloride. Hepatology, 49(5), 1683-1694. https://doi.org/10.1002/hep.22813

Diverse roles of invariant natural killer T cells in liver injury and fibrosis induced by carbon tetrachloride. / Park, Ogyi; Jeong, Won Il; Wang, Lei; Wang, Hua; Lian, Zhe Xiong; Gershwin, M. Eric; Gao, Bin.

In: Hepatology, Vol. 49, No. 5, 05.2009, p. 1683-1694.

Research output: Contribution to journalArticle

Park, O, Jeong, WI, Wang, L, Wang, H, Lian, ZX, Gershwin, ME & Gao, B 2009, 'Diverse roles of invariant natural killer T cells in liver injury and fibrosis induced by carbon tetrachloride', Hepatology, vol. 49, no. 5, pp. 1683-1694. https://doi.org/10.1002/hep.22813
Park, Ogyi ; Jeong, Won Il ; Wang, Lei ; Wang, Hua ; Lian, Zhe Xiong ; Gershwin, M. Eric ; Gao, Bin. / Diverse roles of invariant natural killer T cells in liver injury and fibrosis induced by carbon tetrachloride. In: Hepatology. 2009 ; Vol. 49, No. 5. pp. 1683-1694.
@article{900a9ae5ec914e938188adf7d7bbc09c,
title = "Diverse roles of invariant natural killer T cells in liver injury and fibrosis induced by carbon tetrachloride",
abstract = "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 (CCl4)-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 α-galactosylceramide (α-GalCer) accelerates CCl4-induced acute liver injury and fibrosis. In contrast, chronic CCl4 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 CCl4 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 α-GalCer treatment had little effect on liver injury and fibrosis, which is attributable to iNKT tolerance after α-GalCer injection. Conclusion: Natural activation of hepatic iNKT cells inhibits, whereas strong activation of iNKT cells by α-GalCer accelerates CCl4-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.",
author = "Ogyi Park and Jeong, {Won Il} and Lei Wang and Hua Wang and Lian, {Zhe Xiong} and Gershwin, {M. Eric} and Bin Gao",
year = "2009",
month = "5",
doi = "10.1002/hep.22813",
language = "English (US)",
volume = "49",
pages = "1683--1694",
journal = "Hepatology",
issn = "0270-9139",
publisher = "John Wiley and Sons Ltd",
number = "5",

}

TY - JOUR

T1 - Diverse roles of invariant natural killer T cells in liver injury and fibrosis induced by carbon tetrachloride

AU - Park, Ogyi

AU - Jeong, Won Il

AU - Wang, Lei

AU - Wang, Hua

AU - Lian, Zhe Xiong

AU - Gershwin, M. Eric

AU - Gao, Bin

PY - 2009/5

Y1 - 2009/5

N2 - 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 (CCl4)-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 α-galactosylceramide (α-GalCer) accelerates CCl4-induced acute liver injury and fibrosis. In contrast, chronic CCl4 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 CCl4 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 α-GalCer treatment had little effect on liver injury and fibrosis, which is attributable to iNKT tolerance after α-GalCer injection. Conclusion: Natural activation of hepatic iNKT cells inhibits, whereas strong activation of iNKT cells by α-GalCer accelerates CCl4-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.

AB - 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 (CCl4)-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 α-galactosylceramide (α-GalCer) accelerates CCl4-induced acute liver injury and fibrosis. In contrast, chronic CCl4 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 CCl4 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 α-GalCer treatment had little effect on liver injury and fibrosis, which is attributable to iNKT tolerance after α-GalCer injection. Conclusion: Natural activation of hepatic iNKT cells inhibits, whereas strong activation of iNKT cells by α-GalCer accelerates CCl4-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.

UR - http://www.scopus.com/inward/record.url?scp=66149098871&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=66149098871&partnerID=8YFLogxK

U2 - 10.1002/hep.22813

DO - 10.1002/hep.22813

M3 - Article

C2 - 19205035

AN - SCOPUS:66149098871

VL - 49

SP - 1683

EP - 1694

JO - Hepatology

JF - Hepatology

SN - 0270-9139

IS - 5

ER -