Accumulation of natural killer T cells in progressive nonalcoholic fatty liver disease.
Liver inflammation is greater in nonalcoholic steatohepatitis (NASH) than steatosis, suggesting that immune responses contribute to nonalcoholic fatty liver disease (NAFLD) progression. Livers normally contain many natural killer T (NKT) cells that produce factors that modulate inflammatory and fibrogenic responses. Such cells are relatively depleted in steatosis, but their status in more advanced NAFLD is uncertain. We hypothesized that NKT cells accumulate and promote fibrosis progression in NASH. We aimed to determine if livers become enriched with NKT cells during NASH-related fibrosis; identify responsible mechanisms; and assess if NKT cells stimulate fibrogenesis. NKT cells were analyzed in wildtype mice and Patched-deficient (Ptc(+/-)) mice with an overly active Hedgehog (Hh) pathway, before and after feeding methionine choline-deficient (MCD) diets to induce NASH-related fibrosis. Effects of NKT cell-derived factors on hepatic stellate cells (HSC) were examined and fibrogenesis was evaluated in CD1d-deficient mice that lack NKT cells. NKT cells were quantified in human cirrhotic and nondiseased livers. During NASH-related fibrogenesis in wildtype mice, Hh pathway activation occurred, leading to induction of factors that promoted NKT cell recruitment, retention, and viability, plus liver enrichment with NKT cells. Ptc(+/-) mice accumulated more NKT cells and developed worse liver fibrosis; CD1d-deficient mice that lack NKT cells were protected from fibrosis. NKT cell-conditioned medium stimulated HSC to become myofibroblastic. Liver explants were 2-fold enriched with NKT cells in patients with non-NASH cirrhosis, and 4-fold enriched in patients with NASH cirrhosis.


CONCLUSIONS
Hh pathway activation leads to hepatic enrichment with NKT cells that contribute to fibrosis progression in NASH.
Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
Wing-Kin
WK
Syn
Ye Htun
YH
Oo
Thiago A
TA
Pereira
Gamze F
GF
Karaca
Youngmi
Y
Jung
Alessia
A
Omenetti
Rafal P
RP
Witek
Steve S
SS
Choi
Cynthia D
CD
Guy
Caitlin M
CM
Fearing
Vanessa
V
Teaberry
Fausto E L
FE
Pereira
David H
DH
Adams
Anna Mae
AM
Diehl
D000818:Animals; D002796:Choline Deficiency / Q000150:complications; D005234:Fatty Liver / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D053823:Hedgehog Proteins / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000502:physiology; D006801:Humans; D008099:Liver / Q000276:immunology* / Q000473:pathology; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000502:physiology*; D015398:Signal Transduction
D053823:Hedgehog Proteins; D008715:Methionine