Increased hepatic CD1d has also been noted in patients

with severe NASH.24 Thus, factors that promote NKT cell recruitment, retention, and viability are induced in human and rodent livers buy Selumetinib with NASH-related fibrosis. Hh-pathway activation plays an important role in this process because a genetic manipulation that increases Hh-pathway activity in murine livers exacerbates NASH-related enrichment of liver NKT cells. Hh-signaling may also mediate hepatic NKT cell accumulation in human NASH given the striking correlation between hepatic Hh-pathway activity and the level of enrichment of liver mononuclear cells with NKT cells in patients with NAFLD-related cirrhosis. Our work also suggests that NKT cells actively promote fibrogenesis in NASH because CD1d-deficient mice that lack NKT cells are protected from NASH-related fibrosis and treatment of mouse primary HSCs with conditioned medium from LMNC that contained αGalCer-activated NKT cells stimulated stellate cells to become myofibroblastic. Previously, we showed that primary liver NKT cells from mice produce Shh, and that Shh stimulates NKT cells to produce the profibrogenic cytokines, IL-4 and IL-13.29 Shh also directly stimulates

myofibroblastic activation of HSCs and promotes the proliferation and survival of liver myofibroblasts.36 Ptc+/− KU57788 mice develop worse fibrosis after either bile duct ligation27 or MCD diets.39 Others have reported that IL-13 production increases in mice with NASH-fibrosis, and shown that treatments that neutralize IL-13 reduce fibrogenesis.45 Likewise, inhibiting IL-4 activity is known to diminish hepatic fibrosis in mice.46 Our human studies demonstrate that hepatic enrichment with NKT cells is a feature of cirrhosis. Definitive NKT cell enrichment was observed in patients with NASH-related cirrhosis, in whom we detected a 4 to 5-fold relative increase

in liver NKT cells. The present study confirms the previous reports that increased hepatic expression of CD1d occurs in advanced NAFLD, raising the possibility that antigen presentation to NKT cells may Dapagliflozin be enhanced. This is intriguing because CD1d presents lipid antigens to NKT cells and lipid homeostasis is abnormal in NAFLD. However, further research is needed to determine if and why there might be disease-related differences in hepatic accumulation of NKT cells. Additional studies to address the possibility that NKT cells may interact with other types of innate immune cells to modulate fibrosis progression are also justified because CD56(+)/CD3(−) cells (i.e., NK cells) were relatively depleted in the human cirrhotic livers that we examined, and liver NK cells are thought to serve antifibrogenic functions.6 Also, it has been suggested that liver macrophages, which are a rich source of immunomodulatory cytokines, may be altered in NASH,18 and this could further influence fibrotic activity.