Abstract
Inflammation is a common characteristic of chronic liver disease (CLD). Inflammasomes are multiprotein complexes that can sense and recognize various exogenous and endogenous danger signals, eventually activating interleukin (IL)-1β and IL-18. The sensor component of the inflammasome system is a nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs). The NLRs family pyrin domain containing 3 (NLRP3) inflammasome has been involved in the initiation and progression of CLD. However, the molecular mechanisms by which it triggers liver inflammation and damage remain unclear. Here, we focus on recent advances on the potential role of NLRP3 inflammasome activation in the progression of CLD, including viral hepatitis, non-alcoholic steatohepatitis and alcoholic liver disease, and in particular, its ability to alleviate liver inflammation in animal models. Additionally, we also discuss various pharmacological inhibitors identifying the NLRP3 inflammasome signaling cascade as novel therapeutic targets in the treatment of CLD. In summary, this review summarizes the relevance of the NLRP3 inflammasome in the initiation and progression of CLD, and provides critical targets to suppress the development of CLD in clinical management.
Highlights
Inflammasomes are cytoplasmic multiprotein complexes responsible for caspase-1 activation with the subsequent production of the cytokines interleukin (IL)-1β and IL-18, and the initiation of the inflammatory cell death termed pyroptosis (Figure 1)
As outlined in this review, there is emerging evidence that NLRs family pyrin domain containing 3 (NLRP3) inflammasome activation is involved in the pathogenesis of chronic liver disease (CLD)
Some inhibitors of the NLRP3 inflammasome have already been processed in clinical research in phase 1 and phase 2 trials in various subjects including healthy volunteers and patients with CLD
Summary
Inflammasomes are cytoplasmic multiprotein complexes responsible for caspase-1 (casp1) activation with the subsequent production of the cytokines interleukin (IL)-1β and IL-18, and the initiation of the inflammatory cell death termed pyroptosis (Figure 1). Using RNA sequencing analysis of liver biopsies in HCV-infected patient, they revealed that HCV triggering of these signaling pathways upregulated proinflammatory cytokine and immune-regulatory gene expression networks [11] These works provide multiple lines of evidence to demonstrate that IL-1β maturation and secretion by KCs confers hepatic inflammation via HCV-induced inflammasome signaling through a potassium efflux [33]. Further study by Olteanu et al uncovered that selective deficiency of IL-1α in KCs reduced hepatic inflammation and the mRNA levels of various proinflammatory cytokines including TNFα, IL-1α, IL-1β, IL-6, and serum amyloid A1 in the liver, which may protect against steatohepatitis development [45] In this model, there is no direct evidence to show that IL-1α production in KCs is inflammsome dependent.
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