title: NKp46(+) natural killer cells attenuate metabolism-induced hepatic fibrosis by regulating macrophage activation in mice.
abstract: Nonalcoholic steatohepatitis (NASH) affects 3%-5% of the U.S. population, having severe clinical complications to the development of fibrosis and end-stage liver diseases, such as cirrhosis and hepatocellular carcinoma. A critical cause of NASH is chronic systemic inflammation promoted by innate immune cells, such as liver macrophages (Mϕ) and natural killer (NK) cells. However, little is known about how the crosstalk between Mϕ and NK cells contributes to regulate NASH progression to fibrosis. In this report, we demonstrate that NKp46(+) cells play an important role in preventing NASH progression to fibrosis by regulating M1/M2 polarization of liver Mϕ. Using a murine model of NASH, we demonstrate that DX5(+)NKp46(+) NK cells are increased during disease and play a role in polarizing Mϕ toward M1-like phenotypes. This NK's immunoregulatory function depends on the production of interferon-gamma (IFN-γ), but not by granzyme-mediated cytolytic activity. Notably, depletion of NKp46(+) cells promotes the development of fibrosis with increased expression of profibrogenic genes as well as skewed M2 Mϕ phenotypes in hepatic tissues.
  
  
  CONCLUSIONS
  NK cell-derived IFN-γ may be essential for maintaining a balanced inflammatory environment that promotes tissue integrity and limiting NASH progression to fibrosis.
authors.affiliation: Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, VA.
authors.forename: Annie-Carole
authors.initials: AC
authors.lastname: Tosello-Trampont
authors.affiliation: Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, VA.|Department of Microbiology, Immunology and Cancer Biology, Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, VA.
authors.forename: Peter
authors.initials: P
authors.lastname: Krueger
authors.affiliation: Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, VA.|Department of Microbiology, Immunology and Cancer Biology, Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, VA.
authors.forename: Sowmya
authors.initials: S
authors.lastname: Narayanan
authors.affiliation: Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, VA.
authors.forename: Susan G
authors.initials: SG
authors.lastname: Landes
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA.
authors.forename: Norbert
authors.initials: N
authors.lastname: Leitinger
authors.affiliation: Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, VA.|Department of Microbiology, Immunology and Cancer Biology, Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, VA.
authors.forename: Young S
authors.initials: YS
authors.lastname: Hahn
mesh_terms: D000818:Animals; D016923:Cell Death; D003094:Collagen / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D005355:Fibrosis; D055166:Hepatic Stellate Cells / Q000378:metabolism; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000502:physiology*; D008099:Liver / Q000276:immunology* / Q000473:pathology; D008262:Macrophage Activation; D008264:Macrophages / Q000502:physiology*; D008810:Mice, Inbred C57BL; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000276:immunology* / Q000473:pathology; D010641:Phenotype; D020239:Receptor Cross-Talk; D050378:T-Lymphocytes, Regulatory; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: C112260:NCR1 protein, human; D055627:Natural Cytotoxicity Triggering Receptor 1; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma; D003094:Collagen