Hepatitis C: From inflammatory pathogenesis to anti-inflammatory/hepatoprotective therapy

Abstract

Hepatitis C virus (HCV) infection commonly causes progressive liver diseases that deteriorate from chronic inflammation to fibrosis, cirrhosis and even to hepatocellular carcinoma. A long-term, persistent and uncontrolled inflammatory response is a hallmark of these diseases and further leads to hepatic injury and more severe disease progression. The levels of inflammatory cytokines and chemokines change with the states of infection and treatment, and therefore, they may serve as candidate biomarkers for disease progression and therapeutic effects. The mechanisms of HCV-induced inflammation involve classic pathogen pattern recognition, inflammasome activation, intrahepatic inflammatory cascade response, and oxidative and endoplasmic reticulum stress. Direct-acting antivirals (DAAs) are the first-choice therapy for effectively eliminating HCV, but DAAs alone are not sufficient to block the uncontrolled inflammation and severe liver injury in HCV-infected individuals. Some patients who achieve a sustained virologic response after DAA therapy are still at a long-term risk for progression to liver cirrhosis and hepatocellular carcinoma. Therefore, coupling with anti-inflammatory/hepatoprotective agents with anti-HCV effects is a promising therapeutic regimen for these patients during or after treatment with DAAs. In this review, we discuss the relationship between inflammatory mediators and HCV infection, summarize the mechanisms of HCV-induced inflammation, and describe the potential roles of anti-inflammatory/hepatoprotective drugs with anti-HCV activity in the treatment of advanced HCV infection.

Keywords: Anti-inflammatory and hepatoprotective therapy; Hepatitis C virus infection; Inflammatory pathogenesis; Liver disease.

Figure 1

Mechanisms of hepatitis C virus-induced inflammation. Hepatitis C virus (HCV) RNA triggers Toll-like receptor mediated nuclear factor (NF)-κB activation and inflammatory cytokine release, while HCV proteins mainly lead to oxidative and endoplasmic reticulum stress and potassium efflux, causing the Nod-like receptor pyrin domain containing inflammasome activation. The released inflammatory factors bind to their corresponding receptors and then directly induce NF-κB activation or indirectly lead to signalling pathway mediated downstream inflammatory response. HCV: Hepatitis C virus; ERS: Endoplasmic reticulum stress; AP-1: Activating protein-1; ASC: Apoptosis-associated speck-like protein containing CARD; DAMP: Damage associated molecular patterns; mtDNA: Mitochondrial DNA; MyD88: Myeloid differentiation factor 88; NLRP3: Nod-like receptor pyrin domain containing 3; ROS: Reactive oxygen species; vRNA: Viral RNA; TLR: Toll-like receptor; TNF-α: Tumor necrosis factor-α; IL: Interleukin.

Figure 2

Inflammatory cascade responses in the hepatic microenvironment. Crosstalk among parenchymal cells (hepatocytes), non-parenchymal liver cells (Kupffer cells and hepatic stellate cells) and recruited immune cells (macrophages, mast cells, dendritic cells and natural killer cells) plus hepatitis C virus replication in the hepatic microenvironment mediates inflammatory cascade signalling and exacerbates liver injury and disease progression. HSC: Hepatic stellate cells; NK: Natural killer; HCV: Hepatitis C virus.

Figure 3

Promising anti-inflammatory/hepatoprotective agents for chronic hepatitis C. HCV: Hepatitis C virus; IFN: Interferon; NS: Non-structural; HO-1: Heme oxygenase-1; TLR: Toll-like receptor.