Chemokine Receptor CXCR6-dependent Hepatic NK T Cell Accumulation Promotes Inflammation and Liver Fibrosis

J Immunol. 2013 May 15;190(10):5226-36. doi: 10.4049/jimmunol.1202909. Epub 2013 Apr 17.

Abstract

Chronic liver injury characteristically results in hepatic inflammation, which represents a prerequisite for organ fibrosis. Although NKT cells are abundantly present in liver and involved in hepatic inflammation, molecular mechanisms of their recruitment in liver fibrosis remained elusive. We hypothesized that chemokine receptor CXCR6 and its ligand CXCL16 control NKT cell migration and functionality in liver fibrosis. In patients with chronic liver diseases (n = 58), CXCR6 and CXCL16 expression was intrahepatically upregulated compared with controls. In murine liver, Cxcl16 was strongly expressed by endothelium and macrophages, whereas lymphocyte populations (NKT, NK, CD4 T, CD8 T cells) expressed CXCR6. Intravital two-photon microscopy imaging of Cxcr6(+/gfp) and Cxcr6(gfp/gfp) mice and chemotaxis studies in vitro revealed that CXCR6 specifically controls hepatic NKT cell accumulation during the early response upon experimental liver damage. Hepatic invariant NKT cells expressed distinct proinflammatory cytokines including IFN-γ and IL-4 upon injury. CXCR6-deficient mice were protected from liver fibrosis progression in two independent experimental models. Macrophage infiltration and protein levels of inflammatory cytokines IFN-γ, TNF-α, and IL-4 were also reduced in fibrotic livers of Cxcr6(-/-) mice, corroborating that hepatic NKT cells provide essential cytokine signals perpetuating hepatic inflammation and fibrogenesis. Adoptive transfer of NKT cells, but not CD4 T cells, isolated from wild type livers restored hepatic fibrosis in Cxcr6(-/-) mice upon experimental steatohepatitis. Our results demonstrate that hepatic NKT cells accumulate CXCR6-dependent early upon injury, thereby accentuating the inflammatory response in the liver and promoting hepatic fibrogenesis. Interfering with CXCR6/CXCL16 might therefore bear therapeutic potential in liver fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • Cell Movement
  • Cells, Cultured
  • Chemokine CXCL16
  • Chemokine CXCL6 / biosynthesis
  • Chemokine CXCL6 / blood
  • Chemokine CXCL6 / metabolism*
  • Fatty Liver
  • Hepatocytes / immunology
  • Humans
  • Inflammation / immunology
  • Interferon-gamma / biosynthesis
  • Interleukin-4 / biosynthesis
  • Liver / immunology
  • Liver / injuries
  • Liver / metabolism
  • Liver Cirrhosis / immunology*
  • Liver Cirrhosis / metabolism
  • Liver Diseases / metabolism
  • Macrophages / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Natural Killer T-Cells / immunology*
  • Natural Killer T-Cells / metabolism
  • Receptors, CXCR / biosynthesis
  • Receptors, CXCR / genetics
  • Receptors, CXCR / metabolism*
  • Receptors, CXCR6
  • Up-Regulation

Substances

  • Chemokine CXCL16
  • Chemokine CXCL6
  • Cxcl16 protein, mouse
  • Cxcr6 protein, mouse
  • Receptors, CXCR
  • Receptors, CXCR6
  • Interleukin-4
  • Interferon-gamma