Absence of invariant natural killer T cells deteriorates liver inflammation and fibrosis in mice fed high-fat diet.
BACKGROUND
Invariant natural killer T (iNKT) cells have been suggested to play critical roles in a wide range of immune responses by acting in a proinflammatory or anti-inflammatory manner. Nonalcoholic steatohepatitis (NASH) is a chronic liver disease progressing to advanced cirrhosis and hepatocellular carcinoma. Despite the abundance of iNKT cells in the liver, their role in the pathogenesis of NASH remains obscure. Here, we investigated their role in the development of diet-induced steatosis/steatohepatitis.


METHODS
We used BALB/c wild-type mice and Jα18-deficient (KO) mice lacking iNKT cells fed either a normal diet or a high-fat diet (HFD). The liver and blood were collected from these mice to examine liver inflammation, steatosis, and fibrosis at the indicated time points.


RESULTS
KO mice fed the HFD, compared with control mice fed the HFD, exhibited a clearly higher serum alanine aminotransferase level and a greater number of hepatic inflammatory foci, although there was no significant difference in hepatic lipid retention between these groups of mice. The HFD enhanced hepatic messenger RNA expression of inflammatory cytokines and chemokines in KO but not in control mice. The HFD also increased the proportion of hepatic CD4 T cells and CD8 T cells that composed hepatic inflammatory foci in KO mice, but not in the controls. Prolonged feeding with the HFD augmented liver fibrosis in KO but not in control mice.


CONCLUSIONS
These findings indicate that iNKT cells play a protective role against liver inflammation progressing to fibrosis, but not against steatosis, enhanced by dietary excess fat, suggesting a key role of these cells in NASH pathogenesis.
Miyagi
Takuya
T
Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.
Takehara
Tetsuo
T
Uemura
Akio
A
Nishio
Kumiko
K
Shimizu
Satoshi
S
Kodama
Takahiro
T
Hikita
Hayato
H
Li
Wei
W
Sasakawa
Akira
A
Tatsumi
Tomohide
T
Ohkawa
Kazuyoshi
K
Kanto
Tatsuya
T
Hiramatsu
Naoki
N
Hayashi
Norio
N
D000818:Animals; D004041:Dietary Fats / Q000633:toxicity; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000276:immunology / Q000503:physiopathology*; D007249:Inflammation / Q000276:immunology / Q000503:physiopathology; D008099:Liver / Q000503:physiopathology*; D008103:Liver Cirrhosis / Q000276:immunology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D013997:Time Factors
D004041:Dietary Fats; D016693:Receptors, Antigen, T-Cell, alpha-beta