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-1high 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-1high 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.

S100A4Gene is Crucial for Methionine-Choline-Deficient Diet-Induced Non-Alcoholic Fatty Liver Disease in Mice

“… 6 A total of 25 calcium-binding S100 family members, namely S100A1–18, hair hyaluronin, keratin fibrin, repetin, S100B, S100P, S100Z, and S100G, have been currently identified. 7 As indicated by Mukai, et al, 8 S100A8 could induce the upregulation of tumor necrosis factor-alpha (TNF-α) in CXCR2-expressing CD11b + Gr-1 high cells, thereby aggravating hepatitis in mice. In addition, Liu, et al 9 also found that expression levels of S100A9 was significantly elevated in patients with non-alcoholic fatty liver, which were suggested to be even higher in patients with NASH, highlighting the involvement of S100 protein in NAFLD progression.…”

Conophylline inhibits high fat diet-induced non-alcoholic fatty liver disease in mice

“…Although a methionine-choline-deficient diet has been shown to induce steatohepatitis, which is morphologically similar to NASH, it does not lead to body weight gain and obesity [16]. On the other hand, mice on high-fat diets have been used as NAFLD models [17, 18], and little is known about CnP-mediated attenuation of NAFLD in high-fat diet mouse model.…”

Lipotoxicity pathways intersect in hepatocytes: Endoplasmic reticulum stress, c‐Jun N‐terminal kinase‐1, and death receptors

“…For example, TRAIL −/− mice are protected from inflammation when subjected to a high fat–high fructose diet through the attenuation of both hepatocellular death and macrophage activation . Tumor necrosis factor α is also produced through the calcium and zinc binding protein S100A8 as an endogenous ligand for Toll‐like receptor‐4 in bone marrow‐derived macrophages, thereby contributing to NASH‐associated inflammation …”

“…46 Tumor necrosis factor α is also produced through the calcium and zinc binding protein S100A8 as an endogenous ligand for Toll-like receptor-4 in bone marrow-derived macrophages, thereby contributing to NASH-associated inflammation. 47…”