Liver fibrosis is a scarring process in which excess connective tissue accumulates in the liver, leading to loss of liver function. It can result from a variety of causes, such as viral hepatitis, alcohol abuse, and non-alcoholic fatty liver disease. Treatment focuses on addressing the underlying cause and preventing progression to cirrhosis. Pyroptosis is a highly inflammatory form of programmed cell death. It is initiated by inflammasomes, which are intracellular protein complexes that sense danger signals and activate caspase-1. And Caspase-4,5,11 directly lead to pyroptosis. This triggers the release of inflammatory cytokines, such as IL-1β and IL-18, and leads to cell swelling and rupture. Pyroptosis has been linked to liver fibrosis in some cases. During pyroptosis, it has been discovered that HSCs can increase the expression of genes linked to fibrosis.
Angiotensin II is a hormone that is part of the renin-angiotensin-aldosterone system. It is produced by the cleavage of angiotensin I by the enzyme ACE. Angiotensin II has been shown to play a role in liver fibrosis, inflammation, and steatosis. It promotes the activation of hepatic stellate cells, producing extracellular matrix proteins and fibrosis. Angiotensin II also stimulates pro-inflammatory cytokines and oxidative stress, which contribute to liver damage. It is hypothesized that AngII can activate NLRP3 inflammasomes and induce pyroptosis in HSC-LX2. However, it remains unclear whether pyroptosis induced by AngII is regulated by the classical or non-classical pathway.
Researchers from Zhejiang Chinese Medical University: Dr. Ze-yu Xie, Dr.Yi-xiao Xu, and led by Professor Li Yao pursued to specify the regulatory pathway of AngII-induced pyroptosis, and offered new insights on pyroptosis, in the hope to discover a new therapeutic approach for liver fibrosis. The new research work is now published in the peer-reviewed journal Life Sciences.
The research team initially stimulated HSC-LX2 cells with AngII and found high protein and mRNA levels of α-SMA (a hallmark of liver fibrosis), as well as raised levels of ROS and inflammatory proteins IL-18 and IL-1β. These findings imply that AngII can activate HSC-LX2. Moreover, they looked into the genes and proteins connected to the traditional pyroptosis pathway and discovered that the expression of NLRP3, Caspase-1, and ASC was increased following AngII treatment compared to control. Their investigation into how AngII affected the growth of HSC-LX2 cells revealed that the expression of Caspases-4 and 5 was markedly increased following AngII treatment. Treating with ROS inhibitors (NAC), the authors found a downregulation of NLRP3, Caspase-1, and ASC genes and proteins compared to the AngII group. They therefore came to the tentative assumption that the traditional route mediated by NLRP3/Caspase-1 was responsible for the HSC-LX2 pyroptosis triggered by AngII-ROS. In the human body, Caspase-11’s homologous genes are Caspases-4 and 5. According to their hypothesis, AngII might cause pyroptosis in HSC-LX2 cells by generating ROS, which would then activate Caspases-4 and 5. While suppressing GSDMD, researchers discovered that NSA might downregulate Caspases-4 and 5. There are no specific inhibitors of Caspases-4 and 5, so NSA was utilized as a substitute. They also found that AngII increases ROS generation in HSC-LX2 cells, and ROS inhibitors can reduce the expression of Caspases-4 and 5. Hence, they draw the conclusion that unlike LPS, AngII-ROS may activate Caspases-4 and 5.
Therefore, targeting pyroptosis may be a potential therapeutic strategy for the treatment of liver fibrosis. However, further research is needed to fully understand the mechanisms by which pyroptosis contributes to liver fibrosis and to develop effective pyroptosis-targeting therapies for liver fibrosis. In a nutshell, the findings of Zhejiang Chinese Medical University scientists showed that AngII-ROS coordinated the conventional route, which is mediated by NLRP3 and Caspase- 1, with the non-classical pathway, which is mediated by Caspases-4 and 5, to generate HSC-LX2 pyroptosis. The results of this study lay the groundwork for more research and new lines of inquiry in order to fully comprehend the mechanism of pyroptosis and create cutting-edge liver fibrosis treatment plans.
Xie ZY, Xu YX, Yao L. Angiotensin II can trigger HSC-LX2 pyroptosis through both classical and non-classical pathways. Life Sciences. 2022 Oct 15;307:120878.