TGF-beta activates NLRP3 inflammasome by an autocrine production of TGF-beta in LX-2 human hepatic stellate cells

Inflammation contributes to the pathogenesis of liver disease, and inflammasome activation has been identified as a major contributor to the amplification of liver inflammation. Transforming growth factor-beta (TGF-beta) is a key regulator of liver physiology, contributing to all stages of liver disease. We investigated whether TGF-beta is involved in inflammasome-mediated fibrosis in hepatic stellate cells. Treatment with TGF-beta increased priming of NLRP3 inflammasome signaling by increasing NLRP3 levels and activating TAK1-NF-kB signaling. Moreover, TGF-beta increased the expression of p-Smad2/3-NOX4 in LX-2 cells and consequently increased ROS content, which is a trigger for NLRP3 inflammasome activation. Elevated expression of NEK7 and active caspase-1 was also shown in TGF-beta-induced LX-2 cells, and this level was reduced by (5Z)-oxozeaenol, a TAK inhibitor. Finally, TGF-beta-treated cells significantly increased TGF-beta secretion levels, and their production was inhibited by IL-1 beta receptor antagonist treatment. In conclusion, TGF-beta may represent an endogenous danger signal to the active NLRP3 inflammasome, by which IL-1 beta mediates TGF-beta expression in an autocrine manner. Therefore, targeting the NLRP3 inflammasome may be a promising approach for the development of therapies for TGF-beta-induced liver fibrosis.

Automated summary

Inflammation contributes to liver disease, and inflammasome activation plays a major role in amplifying liver inflammation. This study investigated the involvement of transforming growth factor-beta (TGF-beta) in inflammasome-mediated fibrosis in hepatic stellate cells. The results showed that TGF-beta increased the activation of NLRP3 inflammasome signaling and the expression of p-Smad2/3-NOX4, leading to increased ROS content and NLRP3 inflammasome activation. NEK7 and active caspase-1 expression were also elevated in TGF-beta-induced cells. Furthermore, TGF-beta secretion levels were significantly increased, and IL-1 beta receptor antagonist treatment inhibited its production. These findings suggest that TGF-beta may act as a danger signal to activate the NLRP3 inflammasome in an autocrine manner, and targeting the NLRP3 inflammasome could be a promising approach for treating TGF-beta-induced liver fibrosis.