Retinoic acid signaling sensitizes hepatic stellate cells to NK cell killing via upregulation of NK cell activating ligand RAE1.
Hepatic stellate cells (HSCs) store 75% of the body's supply of vitamin A (retinol) and play a key role in liver fibrogenesis. During liver injury, HSCs become activated and susceptible to natural killer (NK) cell killing due to increased expression of the NK cell activating ligand retinoic acid early inducible gene 1 (RAE-1). To study the mechanism by which RAE-1 is upregulated in HSCs during activation, an in vitro model of cultured mouse HSCs was employed. RAE-1 was detected at low levels in quiescent HSCs but upregulated in 4- and 7-day cultured HSCs (early activated HSCs), whereas 21-day cultured HSCs (fully activated HSCs) lost RAE-1 expression. High levels of RAE-1 in 4- and 7-day cultured HSCs correlated with their susceptibility to NK cell killing, which was diminished by treatment with RAE-1 neutralizing antibody. Furthermore, retinoic acid (RA) and retinal dehydrogenase (Raldh) levels were upregulated in early activated HSCs compared with quiescent or fully activated HSCs. Blocking RA synthesis by the Raldh inhibitor or blocking RA signaling by the retinoic acid receptor antagonist abolished upregulation of RAE-1 whereas treatment with RA induced RAE-1 expression in HSCs. In conclusion, during activation, HSCs lose retinol, which is either secreted out or oxidized into RA; the latter stimulates RAE-1 expression and sensitizes early activated HSCs to NK cell killing. In contrast, fully activated HSCs become resistant to NK cell killing because of lack of RAE1 expression, leading to chronic liver fibrosis and disease.
Section on Liver Biology, NIAAA/NIH, 5625 Fishers Lane, Rm. 2S-33, Bethesda, MD 20892, USA. sradaeva@mail.nih.gov
Svetlana
S
Radaeva
Lei
L
Wang
Sergei
S
Radaev
Won-Il
WI
Jeong
Ogyi
O
Park
Bin
B
Gao
D000445:Aldehyde Oxidoreductases / Q000037:antagonists & inhibitors; D000818:Animals; D002478:Cells, Cultured; D007694:Killer Cells, Natural / Q000502:physiology*; D008099:Liver / Q000166:cytology*; D008103:Liver Cirrhosis / Q000503:physiopathology; D051379:Mice; D034521:Nuclear Matrix-Associated Proteins / Q000502:physiology*; D029543:Nucleocytoplasmic Transport Proteins / Q000502:physiology*; D020033:Protein Isoforms / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014212:Tretinoin / Q000502:physiology*; D015854:Up-Regulation
D034521:Nuclear Matrix-Associated Proteins; D029543:Nucleocytoplasmic Transport Proteins; D020033:Protein Isoforms; C490521:Rae1 protein, mouse; D014212:Tretinoin; D000445:Aldehyde Oxidoreductases; C470579:RALDH2 protein, mouse