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NKp46-mediated killing of human and mouse hepatic stellate cells attenuates liver fibrosis
  1. Chamutal Gur1,
  2. Sarit Doron2,
  3. Shlomit Kfir-Erenfeld1,
  4. Elad Horwitz1,
  5. Lina Abu-tair2,
  6. Rifaat Safadi2,
  7. Ofer Mandelboim1
  1. 1The Lautenberg Center for General and Tumor Immunology, Institute for Medical Research Israel Canada (IMRIC), Hebrew University-Hadassah Medical School, Jerusalem, Israel
  2. 2Liver Unit, Hadassah University Medical Center, Jerusalem, Israel
  1. Correspondence to Professor Ofer Mandelboim, The Lautenberg Center for General and Tumor Immunology, Institute for Medical Research Israel Canada (IMRIC), Hadassah Medical School, 91120 Jerusalem, Israel; oferm{at}


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 (NCR1gfp/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.

  • NK
  • NKp46
  • liver fibrosis
  • immune response
  • immunoregulation
  • hepatitis C
  • IBD
  • immunology in hepatology

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  • See Commentary, p 792

  • RS and OM contributed equally to this work.

  • Funding This study was supported by grants from the Israeli Science Foundation and the Israeli Science Foundation (Morasha), the Croatia Israel Research Grant, the MOST-DKFZ Research Grant, the Rosetrees Trust, the Israel Cancer Association (20100003), the ICRF professorship grant and the Association for International Cancer Research (AICR) (all to OM). CG is supported by The Israeli Science Foundation (Morasha).

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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