Inflammasome activation and function in liver disease

Abstract

Inflammation contributes to the pathogenesis of most acute and chronic liver diseases. Inflammasomes are multiprotein complexes that can sense danger signals from damaged cells and pathogens and assemble to mediate caspase-1 activation, which proteolytically activates the cytokines IL-1β and IL-18. In contrast to other inflammatory responses, inflammasome activation uniquely requires two signals to induce inflammation, therefore setting an increased threshold. IL-1β, generated upon caspase-1 activation, provides positive feed-forward stimulation for inflammatory cytokines, thereby amplifying inflammation. Inflammasome activation has been studied in different human and experimental liver diseases and has been identified as a major contributor to hepatocyte damage, immune cell activation and amplification of liver inflammation. In this Review, we discuss the different types of inflammasomes, their activation and biological functions in the context of liver injury and disease progression. Specifically, we focus on the triggers of inflammasome activation in alcoholic steatohepatitis and NASH, chronic HCV infection, ischaemia-reperfusion injury and paracetamol-induced liver injury. The application and translation of these discoveries into therapies promises novel approaches in the treatment of inflammation in liver disease.

Pro-inflammatory signaling by 24,25-dihydroxyvitamin D3 in HepG2 cells

“…Once released, IL-1β has been shown to act in both autocrine and paracrine fashions to increase its own expression (Szabo & Petrasek 2015) as well as the expression of other proinflammatory cytokines, including TNF α (Mandrekar et al 2011), though we did not observe the latter in our studies. IL-1β activates hepatic stellate cells leading to fibrosis (Miura et al 2010) and increases triglyceride accumulation in hepatocytes (Miura et al 2010, Petrasek et al 2012.…”

Protective effect of quercetin on high-fat diet-induced non-alcoholic fatty liver disease in mice is mediated by modulating intestinal microbiota imbalance and related gut-liver axis activation

“…However, it has been recently reported that both activation of dysbiosis-induced TLR-NF-B signaling pathway and oxidative stress-related lipotoxicity are involved in inflammasome response, which regulate the development and progression of NAFLD [9,10,83]. We observed an overexpression of hepatic inflammasome component NLRP3 and the subsequent activation of caspase-1, which could be associated with disease progression as shown in patients with NAFLD [84].…”

HCV genotype 3: a wolf in sheep’s clothing

“…[32] The inflammation may also contribute to the pathogenesis of liver damage. [33] Obesity has also been correlated with a lower SVR rate. [34] Once again, this opens up an interesting way to research the mechanisms involving MS and SVR in these patients.…”