Involvement of Nucleotide-Binding Oligomerization Domain-Like Receptor Family Pyrin Domain Containing 3 Inflammasome in the Pathogenesis of Liver Diseases

Abstract

The inflammasome is widely acknowledged for its crucial role in the pathogenesis of cancers and many neurodegenerative, metabolic, and auto-inflammatory diseases in recent years. Multiple types of inflammasomes exist. However, nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is the most often investigated inflammasome and has come to limelight in recent studies. NLRP3 inflammasome is a multi-protein complex. Its activation can cause the cleavage of inactive pro-caspase-1 into activated caspase-1, that ultimately promotes the transformation of pro-interleukin (IL)-1β and pro-IL-18 into biologically-active IL-1β and IL-18, respectively. These processes lead to the local inflammatory responses and induce pyroptosis, causing disparaging effects. Recently, numerous studies have shown that NLRP3 inflammasome plays an important role in the pathogenesis of liver diseases, including non-alcoholic fatty liver disease, liver fibrosis, cirrhosis, and hepatocellular carcinoma. Liver diseases have become a severe health burden worldwide, and there is adequate evidence indicating that the regulation of NLRP3 inflammasome acts as a guard against hazard to liver. In this review, we provide a straightforward overview of NLRP3 inflammasome as well as several frequent liver diseases. We then discuss the contribution and regulation of NLRP3 inflammasome during the pathogenesis of liver diseases, which may provide an important indication for the prevention and treatment of various liver diseases.

Keywords: NLRP3 inflammasome; cirrhosis; hepatocellular carcinoma; inflammation; liver fibrosis; non-alcoholic fatty liver disease.

FIGURE 1

The structure and activation of NLRP3 inflammasome: NLRP3 inflammasome consists of NLRP3, ASC, and pro-caspase-1. A two-step mechanism leads to NLRP3 inflammasome activation, including the priming and the activation step. During the priming step, TLR, NOD2, or TNFR receives the stimulation induced by extracellular signaling molecules, leading to the activation of NF-κB. NF-κB then promotes the expression of NLRP3, pro-IL-1β, and pro-IL-18. During the activation step, the stimulation like K⁺ efflux, Ca²⁺ mobilization, Na⁺ influx, chloride efflux, ROS, mitochondrial dysfunction, and lysosomal damage leads to the assembly of NLRP3 inflammasome. In the process of NLRP3 inflammasome activation, activated caspase-1 transforms pro-IL-1β and pro-IL-18 into mature IL-1β and IL-18, resulting in the release of inflammatory cytokines. Further, activated caspase-1 dissociates GSDMD to release its N-terminus, form pores in the plasma membrane, and stimulate the occurrence of pyroptosis. ASC, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (CARD); GSDMD, gasdermin D; NF-κB, nuclear factor-κB; NLRP3, nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3; pro-IL-1β, pro-interleukin-1β; pro-IL-18, pro-interleukin-18; ROS, reactive oxygen species; TLR, toll-like receptor; TNFR, tumor necrosis factor receptor.

FIGURE 2

Effect and activity regulation of NLRP3 inflammasome during the pathogenesis of NAFLD: PPAR-δ agonist GW501516 activates PPAR-δ through AMPK/ROS pathway, suppresses NLRP3 inflammasome activation, which ultimately alleviates NAFLD status. Danger factors like high fat and carbohydrate give rise to hepatocyte oxidative stress. This process generates excess ROS leading to the activation of NLRP3 inflammasome. Moreover, NF-κB signaling and ER stress also induce NLRP3 inflammasome activation. These influential factors ultimately aid the progression and pathogenesis of NAFLD. AMPK, AMP-activated protein kinase; ER, endoplasmic reticulum; NAFLD, non-alcoholic fatty liver disease; PPAR-δ, peroxisome proliferator-activated receptors-δ.

FIGURE 3

Role of NLRP3 inflammasome during the different stages of liver diseases NAFLD is the most common form of chronic liver diseases, which can progress to more serious diseases, including liver fibrosis, cirrhosis, and HCC. The regulation of NLRP3 inflammasome activity has significant effect on the pathogenesis of these liver diseases. HCC, hepatocellular carcinoma.