Role of pyroptosis in liver diseases
Introduction
In the process of individual growth and development, cell death can occur at any time. It is a universal life phenomenon in biology, which plays an important role in the growth, development, and homeostasis of multicellular organisms [1]. It is believed that there are two ways of cell death: cell necrosis, and programmed cell death. The latter includes programmed cell death, and apoptosis [2]. In recent years, researchers have found new ways of programmed cell death, including cell swelling, autophagy, and pyroptosis. Unlike apoptosis and necrosis, pyroptosis is dependent on inflammatory caspase-1, and caspase-4/5/11 with inflammation. Caspase is activated by various microbial infections, and several endogenous risk signals. However, pyroptosis plays critical roles in several diseases, including infectious diseases, cardiovascular diseases, central nervous system diseases, and tumors [3], [4], [5], [6]. Therefore, this paper reviews the molecular mechanism of pyroptosis and its role in the pathogenesis and progression of various liver diseases.
Section snippets
History of pyroptosis
The morphological characteristic and function of pyroptosis were first observed in macrophages infected with Gram-negative bacteria called Shigella flexneri in 1992, which was mistaken for the morphological change of apoptosis [7]. Similar phenotypes were firstly observed in macrophages infected with Salmonella in 1999 [8]. Further studies have shown that both selective caspase-1 inhibitors and caspase-1 gene knockout can effectively block the cell death induced by Shigella flexneri, while
Canonical pyroptotic pathways
In terms of mechanism, pyroptotic processes are well preserved in different cell types which have been proved to involve the activation of typical caspase-1 and atypical caspase-4/5/11 (human caspase-4/5, and mouse caspase-11) [20]. Pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) are detected in the typical pyroptotic signaling pathways by the nucleotide-binding oligomerization domain (NOD) like receptor (NLRP3, NLRP1, NLRC4, NLRP9 and NLRP6),
Role of pyroptosis in liver diseases
Generally, moderate pyroptosis regulates to remove infected cells in time. With the increasing incidence of liver diseases, it has recently become a serious health issue. Some liver diseases gradually develop into cirrhosis, as well as liver cancer, which in turn can become a massive threat to human life worldwide [61]. In addition, recent studies have reported that pyroptosis can play significant roles in the progression of liver diseases [62]. During imbalanced intestinal floral condition,
Targeting pyroptosis for the therapeutic implications of liver diseases
Targeting pyroptosis is a promising treatment option for liver diseases, which has been receiving attention to researchers or clinicians worldwide. At present, there are two main strategies to suppress pyroptosis. One is to inhibit NLRP3 inflammasome through the regulatory pathways; for example-MCC950 is called as an NLRP3 inhibitor, which can effectively reduce cholestetic liver injury, and inflammation in bile duct ligation (BDL) mice model [100]. So, this study demonstrated that MCC950
Summary
So far, two types of pyroptosis signaling pathways have been described as typical caspase-1 dependent, and non-abnormal caspase-4/5/11 mediated signaling pathways. New evidence suggests that the NLRP3 inflammasome activation is an important regulator of pyroptosis process, which plays various roles in the development of liver diseases, including NAFLD, ALD, ACLF, HBV and HCV, AIH, HCC, and fibrosis (Fig. 5). However, despite these new developments, little study has been done on pyroptosis until
Declaration of Competing Interest
The authors declare that there is no conflict of interest.
Acknowledgment
We are giving thanks to Molecular Pharmacology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China to conduct this study and for the valuable supports.
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