Hepatitis C virus (HCV) is a well-known pathogen to establish chronic infection leading to end-stage liver disease. The destruction of liver tissues takes its roots under chronic inflammation and proinflammatory signaling in liver microenvironment. The viral proteins interact with certain pattern recognition receptors, including Toll-like receptors, activating the innate immune system to clear the virus. HCV achieves immune evasion through other mechanisms and induce a continuous inflammatory microenvironment via Kupffer cells and Hepatic Stellate cells. This promotes disease progression. The current study aims to elucidate that the role of Toll-like receptor 4 (TLR4) induced innate immune response in chronic inflammation in patients chronically infected with HCV. For this purpose, changes in downstream signaling cascade of TLR4 during chronic HCV infection using peripheral blood mononuclear cells of chronic HCV patients were studied. We found significant increase in expression levels of proinflammatory and profibrotic genes induced by TLR4 Myeloid differentiation factor 88 (MyD88)-dependent pathway between treatment naive and healthy controls, while no significant difference between the expressions of genes involved in TLR4 signaling was found between treatment responders and healthy controls. Interestingly, both TLR4 MyD88-dependent and -independent pathways were found to be operational in nonresponders to interferon treatment. This further strengthens the involvement of innate immune signaling as a leading factor in HCV-mediated liver disease progression and the role of TLR4 MyD88-dependent and -independent pathway in ensuring the conditions for chronic inflammation.

中文翻译：

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在慢性丙型肝炎病毒感染中通过 TLR4 MyD88 依赖性和独立炎症信号诱导促纤维化微环境。

丙型肝炎病毒 (HCV) 是一种众所周知的病原体，可引起慢性感染，导致终末期肝病。肝脏组织的破坏源于肝脏微环境中的慢性炎症和促炎信号。病毒蛋白与某些模式识别受体相互作用，包括 Toll 样受体，激活先天免疫系统以清除病毒。HCV 通过其他机制实现免疫逃避，并通过库普弗细胞和肝星状细胞诱导持续的炎症微环境。这会促进疾病进展。目前的研究旨在阐明 Toll 样受体 4 (TLR4) 在慢性感染 HCV 患者的慢性炎症中诱导先天免疫反应的作用。以此目的，使用慢性 HCV 患者的外周血单核细胞研究了慢性 HCV 感染期间 TLR4 下游信号级联的变化。我们发现未经治疗的对照组和健康对照组之间由 TLR4 髓样分化因子 88 (MyD88) 依赖性途径诱导的促炎和促纤维化基因的表达水平显着增加，而在治疗应答者之间未发现参与 TLR4 信号传导的基因表达水平存在显着差异和健康对照。有趣的是，发现 TLR4 MyD88 依赖性和非依赖性通路在对干扰素治疗无反应的患者中均有效。