Role of inflammatory response in liver diseases: Therapeutic strategies

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.