S100A8 Production in CXCR2-Expressing CD11b+Gr-1high Cells Aggravates Hepatitis in Mice Fed a High-Fat and High-Cholesterol Diet

J Immunol. 2016 Jan 1;196(1):395-406. doi: 10.4049/jimmunol.1402709. Epub 2015 Nov 25.

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease with a spectrum of presentations. S100A8 has been suggested to play a pivotal role as an endogenous immune-activator in inflammatory diseases. In this study, we investigated the involvement of S100A8 in the development of NAFLD. We used a diet model of NAFLD, in which mice were fed either a high-fat and high-cholesterol diet (HFHCD) or a normal diet (ND) as a control. We also assessed liver tissues from patients with NAFLD, including patients with nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). HFHCD-fed mice, but not ND-fed mice, developed steatohepatitis. S100A8 expression was significantly elevated in the livers of HFHCD-fed mice compared with the controls. S100A8 was exclusively expressed in CXCR2-expressing CD11b(+)Gr-1(high) cells, which significantly increased in the livers of HFHCD-fed mice. These cells were F4/80 negative and did not possess a suppressor function. TNF-α expression was enhanced by S100A8 in primary liver leukocytes or a hepatocyte cell line and significantly elevated in the livers of HFHCD-fed mice. TNF-α was primarily produced from CD11b(+)F4/80(+) cells in liver leukocytes in response to S100A8. TNF-α deficiency attenuated hepatitis in HFHCD-fed mice. S100A8 was significantly more expressed in the liver tissues of patients with NASH than in those of patients with NAFL. In conclusion, these results suggest that S100A8 is primarily produced from CXCR2-expressing CD11b(+)Gr-1(high) cells, and it upregulates TNF-α production in CD11b(+)F4/80(+) cells through cellular cross-talk, which is an important mechanism in the development of NAFLD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Animals
  • Antigens, Differentiation / metabolism
  • CD11b Antigen / biosynthesis*
  • Calgranulin A / biosynthesis
  • Calgranulin A / metabolism*
  • Cell Line
  • Chemokine CXCL1 / metabolism
  • Diet, High-Fat
  • Female
  • Hepatitis / immunology*
  • Hepatocytes / metabolism
  • Humans
  • Inflammation / immunology
  • Liver / cytology
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Non-alcoholic Fatty Liver Disease / immunology*
  • Non-alcoholic Fatty Liver Disease / pathology
  • Receptors, Chemokine / biosynthesis*
  • Receptors, Interleukin-8B / biosynthesis*
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism
  • Young Adult

Substances

  • Antigens, Differentiation
  • CD11b Antigen
  • Calgranulin A
  • Chemokine CXCL1
  • Cxcl1 protein, mouse
  • Gr-1 protein, mouse
  • Receptors, Chemokine
  • Receptors, Interleukin-8B
  • S100a8 protein, mouse
  • Tumor Necrosis Factor-alpha
  • monocyte-macrophage differentiation antigen