title: S100A8 Production in CXCR2-Expressing CD11b+Gr-1high Cells Aggravates Hepatitis in Mice Fed a High-Fat and High-Cholesterol Diet.
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.
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan;
authors.forename: Kaori
authors.identifier: http://orcid.org/0000-0003-1043-4577
authors.initials: K
authors.lastname: Mukai
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan;
authors.forename: Takuya
authors.initials: T
authors.lastname: Miyagi
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan;
authors.forename: Kumiko
authors.initials: K
authors.lastname: Nishio
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan;
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Yokoyama
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan;
authors.forename: Teppei
authors.initials: T
authors.lastname: Yoshioka
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan;
authors.forename: Yoshinobu
authors.identifier: http://orcid.org/0000-0002-0624-0449
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan;
authors.forename: Satoshi
authors.identifier: http://orcid.org/0000-0003-3950-783X
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan;
authors.forename: Minoru
authors.initials: M
authors.lastname: Shigekawa
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan;
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Nawa
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan;
authors.forename: Hayato
authors.initials: H
authors.lastname: Hikita
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan;
authors.forename: Ryotaro
authors.identifier: http://orcid.org/0000-0002-1580-607X
authors.initials: R
authors.lastname: Sakamori
authors.affiliation: Osaka Rosai Hospital, Osaka 591-8025, Japan; and.
authors.forename: Harumasa
authors.initials: H
authors.lastname: Yoshihara
authors.affiliation: Ikeda Municipal Hospital, Osaka 563-8510, Japan.
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Imai
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan;
authors.forename: Naoki
authors.identifier: http://orcid.org/0000-0002-8803-4488
authors.initials: N
authors.lastname: Hiramatsu
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan;
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tatsumi
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan; takehara@gh.med.osaka-u.ac.jp.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Takehara
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D039481:CD11b Antigen / Q000096:biosynthesis*; D040501:Calgranulin A / Q000096:biosynthesis / Q000378:metabolism*; D002460:Cell Line; D054360:Chemokine CXCL1 / Q000378:metabolism; D059305:Diet, High-Fat; D005260:Female; D006505:Hepatitis / Q000276:immunology*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology; D008099:Liver / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000276:immunology* / Q000473:pathology; D019707:Receptors, Chemokine / Q000096:biosynthesis*; D023063:Receptors, Interleukin-8B / Q000096:biosynthesis*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D000943:Antigens, Differentiation; D039481:CD11b Antigen; D040501:Calgranulin A; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; C503133:Gr-1 protein, mouse; D019707:Receptors, Chemokine; D023063:Receptors, Interleukin-8B; C086145:S100a8 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C036763:monocyte-macrophage differentiation antigen