Hepatocytes Are Resistant to Cell Death From Canonical and Non-Canonical Inflammasome-Activated Pyroptosis

Abstract

Caspase-1/11 activation induces macrophage pyroptosis, but hepatocytes are resistant to pyroptosis, which we show is mainly due to low levels of caspase-1/11 even after stimulation. Overexpression of caspase-1/11 p10/p20 can induce hepatocyte pyroptosis and cell shrinkage, but cell structure remains relatively intact differently from macrophage pyroptosis.CONCLUSIONS: Our novel findings characterize hepatocyte morphology in pyroptosis and suggest alternative use for canonical/non-canonical inflammasome activation/signaling and subsequent GSDMD cleavage because there is no rapid cell death as in macrophages. Improved understanding and recognition of the role of these pathways in hepatocytes may result in novel therapeutics for a range of liver diseases.

Multi-Omics Analysis Reveals the Protection of Gasdermin D in Concanavalin A-Induced Autoimmune Hepatitis

“…Nevertheless, the mice we used were a whole-body Gsdmd knockout, which left some questions. Some researchers observed that hepatocytes are insensitive to pyroptosis, since GSDMD blockade in the innate immune cell protects against hepatic ischemia-reperfusion injury but the same was not true for hepatocytes ( 56 , 57 ). In contradiction, others demonstrated an essential role of GSDMD-mediated hepatocyte pyroptosis in acute liver failure ( 58 ).…”

The emerging role of pyroptosis-related inflammasome pathway in atherosclerosis

“…The activated caspase-1, in turn, cleaves pro-IL-1β and pro-IL-18 into mature IL-1β and IL-18. Meanwhile, activated caspases can also cleave full-length GSDMD (GSDMD-FL) protein into N-terminal fragments of GSDMD (GSDMD‐NT), which exerts pore-forming function and leads to pyroptotic cell lysis (Song et al 2022 ; Sun et al 2022 ). Most recently, Kayagaki et al found that end‐stage plasma membrane rupture was not a passive osmotic lysis event but was dependent on ninjurin‐1 oligomerization (Kayagaki et al 2021 ).…”

Review: the role of GSDMD in sepsis

“…The study concluded that pyroptosis plays an important role in the development of liver disease, including sepsis-induced liver injury [ 68 ]. Overexpression of the p10/p20 activation domain of caspase-1 or caspase-11 induces typical GSDMD-dependent pyroptosis in hepatocytes but not cell rupture after LPS stimulation in vitro and in vivo death is different [ 69 ]. In addition, Escherichia coli can also enter liver tissue and cause bacterial liver injury, and liver injury and pyroptosis are more severe in CD38 −/− mice, because CD38 deficiency triggers extracellular molecule recognition to activate inflammasome NLRP3-GSDMD-mediated Pyroptosis leads to severe bacterial liver damage [ 70 ].…”