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

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 NAF...

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Published in:The Journal of immunology (1950) 2016-01, Vol.196 (1), p.395-406
Main Authors: Mukai, Kaori, Miyagi, Takuya, Nishio, Kumiko, Yokoyama, Yoshinobu, Yoshioka, Teppei, Saito, Yoshinobu, Tanaka, Satoshi, Shigekawa, Minoru, Nawa, Takatoshi, Hikita, Hayato, Sakamori, Ryotaro, Yoshihara, Harumasa, Imai, Yasuharu, Hiramatsu, Naoki, Tatsumi, Tomohide, Takehara, Tetsuo
Format: Article
Language:English
Subjects:
Adolescent
Adult
Aged
Animals
Antigens, Differentiation - metabolism
Calgranulin A - biosynthesis
Calgranulin A - metabolism
CD11b Antigen - biosynthesis
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
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Summary: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.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1402709