Role of inflammatory response in liver diseases: Therapeutic strategies

Abstract

Inflammation and tumorigenesis are tightly linked pathways impacting cancer development. Inflammasomes are key signalling platforms that detect pathogenic microorganisms, including hepatitis C virus (HCV) infection, and sterile stressors (oxidative stress, insulin resistance, lipotoxicity) able to activate pro-inflammatory cytokines interleukin-1β and IL-18. Most of the inflammasome complexes that have been described to date contain a NOD-like receptor sensor molecule. Redox state and autophagy can regulate inflammasome complex and, depending on the conditions, can be either pro- or anti-apoptotic. Acute and chronic liver diseases are cytokine-driven diseases as several proinflammatory cytokines (IL-1α, IL-1β, tumor necrosis factor-alpha, and IL-6) are critically involved in inflammation, steatosis, fibrosis, and cancer development. NLRP3 inflammasome gain of function aggravates liver disease, resulting in severe liver fibrosis and highlighting this pathway in the pathogenesis of non-alcoholic fatty liver disease. On the other hand, HCV infection is the primary catalyst for progressive liver disease and development of liver cancer. It is well established that HCV-induced IL-1β production by hepatic macrophages plays a critical and central process that promotes liver inflammation and disease. In this review, we aim to clarify the role of the inflammasome in the aggravation of liver disease, and how selective blockade of this main pathway may be a useful strategy to delay fibrosis progression in liver diseases.

Keywords: Caspase-1; Fibrosis; Hepatitis C virus; Inflammasome; Interleukin-1α; Interleukin-1β; Liver disease; NLRP3; Non-alcoholic fatty liver disease; Tumor necrosis factor-alpha.

Figure 1

Hepatic fibrosis caused by the activation of the inflammasome-NLRP3 complex. The accumulation of lipids derived from the metabolic syndrome produces a non-alcoholic steatohepatitis (NASH) that progresses to a non-alcoholic fatty liver disease (NAFLD). The accumulated lipids, fatty acids, cholesterol crystals, among others, produce an alteration in the homeostasis of the liver cells, producing liver damage. Danger-activated molecular patterns (DAMPs) and pathogenic-activated molecular patterns (PAMPs) bind to and activate PRR receptors (TLRs, NLRPs, etc.) in hepatocytes, immune cells, hepatic stellate cells (HSCs), endothelial cells and DCs. Activated TLRs activate the cells and contribute to the release of cytokines that facilitate progression of liver disease. The proinflammatory stimulus facilitates hepatocyte damage, contributing to the secretion of profibrogenic cytokines such as transforming growth factor beta (TGF-β), promoting the activation of HSCs. This activation, in turn, up-regulates transcription of inflammasome-related components, including inactive NLRP3, pro-IL-1β and proIL-18. The second step of inflammation activation is the oligomerization of NLRP3 and subsequent assembly of NLRP3, ASC, and procaspase-1 into a complex. This triggers the transformation of procaspase-1 to caspase-1, as well as the production and secretion of mature IL-1β and IL-18, which produces liver damage and facilitates the progression of hepatic fibrosis.