Toll-Like Receptor 5 Signaling Ameliorates Liver Fibrosis by Inducing Interferon β–Modulated IL-1 Receptor Antagonist in Mice

Abstract

Bacterial flagellin, recognized by cell surface of Toll-like receptor (TLR) 5, is a potent activator of many types of cells, leading to the activation of innate or adaptive immunity, which are pivotal in regulating fibrotic process. However, the exact role of TLR5 signaling in hepatic fibrogenesis remains unclear, and this study aims to elucidate its underlying mechanisms. Flagellin was injected to hepatotoxin-and cholestasis-induced liver fibrosis murine models. Flagellin-induced TLR5 activation significantly decreased the severity of liver fibrosis. Interestingly, the expression levels of IL-1 receptor antagonist (IL1RN) and interferon (IFN)b markedly increased in fibrotic livers on flagellin treatment. Consistently, in vivo activation of TLR5 signaling markedly increased IFNb and IL1RN expression in the livers. Notably, flagellin injection significantly exacerbated the severity of liver fibrosis in IFN-a/b receptor 1 (IFNAR1) knockout mice. Furthermore, hepatic expression of IL1RN in the fibrotic livers of IFNAR1 knockout mice was significantly lower than those of wild-type mice. In support of these findings, flagellin-mediated IL1RN production is not sufficient to alleviate the severity of hepatic fibroinflammatory responses in IFNAR1-deficient milieu. Finally, hepatic stellate cells treated with IL1RN had significantly decreased cellular activation and its associated fibrogenic responses. Collectively, manipulation of TLR5 signaling may be a promising therapeutic strategy for the treatment of liver fibrosis.

A genetic variant in toll‐like receptor 5 is linked to chemokine levels and hepatocellular carcinoma in steatohepatitis

“…7,22 So far, TLR5, the receptor for bacterial flagellin, has been implicated in progression of liver disease mainly in animal models. 23,24 In viral hepatitis B, the TLR5 rs5744174 TT genotype has been associated with HBe antigen to anti-HBe seroconversion, 25 with development of HCC in HBe antigen positive patients, 26 but also independently of HBe antigen status, 27 indicating that TLR5 21 our data support a hypothesis that flagellin is translocated from the intestine in cirrhotic patients and triggers via TLR5 an immune response favouring HCC development.…”

A Network Pharmacology Approach to Explore the Mechanisms of Shugan Jianpi Formula in Liver Fibrosis

“…By autophosphorylation, AKT1 regulates key signaling pathways such as the Janus kinase-signal transducer and activator of transcription (JAK-STAT), apoptosis, mammalian target of rapamycin, and mitogen-activated protein kinase (MAPK) signaling pathways [33,34], regulates apoptosis and related proteins, thus affecting the process of LF. IL-1β, a critical mediator of the inflammatory response, and can promote the proliferation and differentiation of HSCs in a dosedependent manner, leading to the occurrence and development of LF [35,36]. rough qPCR, we confirmed that SCJPF can downregulate the expression of IL-6, TP53, AKT1, and IL-1β in the pathogenesis of LF to play a role in the treatment of LF.…”

Predictive Value of The G1–G6 Transcriptomic Molecular Classification of Hepatocellular Carcinoma for its Biological Behavior and Clinicopathological Features in China

“…Tissues were harvested and lysed in cold extraction buffer (RIPA, Beyotime Biotechnology, Shanghai, China) as previously described [14]. Samples were centrifuged at 13,000 × g at 4°C for 15 min, and the protein concentration in the supernatants was measured using the Pierce BCA Protein Assay kit (Thermo Fisher Scienti c Inc., Waltham, IL, USA) according to the manufacturer's protocol.…”