Abstract
Toll-like receptor 4 (TLR4) signaling plays a key role in liver inflammation and fibrosis. The therapeutic effects of eritoran, a TLR4 antagonist, in mice with chronic liver injury remained unclear. C57BL/6 mice were fed a fast-food diet (FFD) or treated with carbon tetrachloride (CCl4) to induce chronic liver injury. Eritoran (10 mg/kg) or a vehicle was randomly intraperitoneally administered to the FFD-fed mice and the CCl4-injured mice. Primary mouse liver cells were cultured with lipopolysaccharide (LPS) or eritoran. In both FFD and CCl4 mouse models, eritoran significantly reduced serum ALT levels and decreased hepatic inflammatory cell infiltration without altering hepatic steatosis. Additionally, eritoran attenuated liver fibrosis by decreasing hepatic stellate cells (HSCs) activation and the abundance of α-smooth muscle actin and transforming growth factor-β1. Hepatic TLR4 downstream signaling including MyD88 expression, NF-κB p65 nuclear translocation, p38 and JNK phosphorylation were successfully inhibited by eritoran. In the in vitro study, LPS-induced nuclear translocation of NF-κB in primary HSCs and Kupffer cells was significantly suppressed by eritoran. In conclusion, eritoran attenuated hepatic inflammation and fibrosis by inhibition of the TLR4 signaling pathway in mice with chronic liver injury. Eritoran may serve as a potential drug for chronic liver disease.
Highlights
Chronic liver disease (CLD) is a continuous process of inflammation and the healing process of liver parenchyma which leads to fibrosis and cirrhosis, imposing a high morbidity and mortality burden worldwide [1]
hematoxylin and eosin (H&E) and myeloperoxidase (MPO) staining of the liver sections showed that eritoran treatment significantly reduced lobular inflammation and intrahepatic neutrophil infiltration in the fast-food diet (FFD)-fed mice (Figure 2E,F)
N-terminal kinase (JNK) was reduced after eritoran treatment (Figure 5C). These results demonstrated that the chronic administration of eritoran successfully suppressed the hepatic Toll-like receptor 4 (TLR4) signaling pathway by downregulating the myeloid differentiation factor 88 (MyD88) expression, NF-κB p65 nuclear translocation and phosphorylation of p38 and Jun N-terminal kinase (JNK) in a nonalcoholic steatohepatitis (NASH) mouse model
Summary
Chronic liver disease (CLD) is a continuous process of inflammation and the healing process of liver parenchyma which leads to fibrosis and cirrhosis, imposing a high morbidity and mortality burden worldwide [1]. LPS sensitizes HSCs to transforming growth factor-β (TGF-β) signals, which mediate fibrogenesis through the TLR4–MyD88–NF-κB pathway [11] This evidence suggests that TLR4 signaling plays an important role in hepatic inflammation and fibrosis and promotes the progression of CLD [12]. It has been shown that the binding of eritoran to the TLR4/MD2 complex blocks the activation of NF-κB and the production of proinflammatory cytokines, such as TNF-α and interleukin (IL)-6, both in vivo and in vitro, in response to LPS [14,15,16,17,18]. We examined whether chronic administration of eritoran blocks hepatic TLR4 signaling, the subsequent inflammatory responses and fibrosis in mouse models of chronic liver injury
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