title: NKp46-mediated killing of human and mouse hepatic stellate cells attenuates liver fibrosis.
abstract: BACKGROUND
  Liver fibrosis, which involves activation of hepatic stellate cells (HSC), is a major health problem and is the end outcome of all chronic liver diseases. The liver is populated with lymphocytes, among which are natural killer (NK) cells, whose activity is controlled by inhibitory and activating receptors. NKp46, one of the major NK activating receptors expressed by NK cells, is also a specific NK marker that discriminates NK cells from all other lymphocyte subsets. It recognises viral haemagglutinins and unknown cellular ligands.
  
  
  METHODS
  The anti-fibrotic activity of the NKp46 receptor was assessed in vivo and in vitro using NKp46-deficient mice (NCR1(gfp/gfp)), the carbon tetrachloride model and in vitro NK killing assays. Primary murine and human HSC were stained for the expression of the NKp46 ligand using fusion proteins composed of the extracellular portions of the murine and human NKp46 receptors fused to human IgG1.
  
  
  RESULTS
  It was shown that murine HSC express a ligand for the murine orthologue of the NKp46 receptor, NCR1. NCR1 inhibited liver fibrosis in vivo; in vitro, murine HSC were killed in an NCR1-dependent manner. In humans it was shown that human HSC also express a ligand for the human NKp46 receptor and that the killing of human HSC is NKp46 dependent.
  
  
  CONCLUSIONS
  In addition to NKG2D, NKp46/NCR1 play an important role in inhibition of liver fibrosis. This suggests that fibrosis can be better controlled through the manipulation of NKp46 activity.
authors.affiliation: The Lautenberg Center for General and Tumor Immunology, Institute for Medical Research Israel Canada-IMRIC, Hadassah Medical School, Jerusalem, Israel.
authors.forename: Chamutal
authors.initials: C
authors.lastname: Gur
authors.forename: Sarit
authors.initials: S
authors.lastname: Doron
authors.forename: Shlomit
authors.initials: S
authors.lastname: Kfir-Erenfeld
authors.forename: Elad
authors.initials: E
authors.lastname: Horwitz
authors.forename: Lina
authors.initials: L
authors.lastname: Abu-Tair
authors.forename: Rifaat
authors.initials: R
authors.lastname: Safadi
authors.forename: Ofer
authors.initials: O
authors.lastname: Mandelboim
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000502:physiology; D055166:Hepatic Stellate Cells / Q000502:physiology*; D006801:Humans; D007136:Immunoglobulins / Q000502:physiology; D007694:Killer Cells, Natural / Q000502:physiology; D008103:Liver Cirrhosis / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology
chemical_list: D000950:Antigens, Ly; D007136:Immunoglobulins; C112260:NCR1 protein, human; D055627:Natural Cytotoxicity Triggering Receptor 1; C118384:Ncr1 protein, mouse; D011993:Recombinant Fusion Proteins