The Lipopolysaccharide-Sensing Caspase(s)-4/11 Are Activated in Cirrhosis and Are Causally Associated With Progression to Multi-Organ Injury

Abstract

Graphical AbstractModel of caspase-4/11 activation in cirrhosis. Gut-derived bacterial LPS (1) enters the portal circulation after translocation across the gut epithelium and is internalized by hepatocytes. Cytoplasmic LPS is recognized by caspase-4/11 (2), which undergoes self-activation upon ligand binding. The activity of caspase-4/11 is enhanced by endoplasmic reticulum stress (3), which occurs in fibrosis/cirrhosis, leading to “sensitization” of this pathway. Active caspase-4/11 cleaves the dimeric protein Gasdermin D (GSDMD) (4), and freeing the N-terminal domain to migrate to the plasma membrane and form GSDMD N-terminal octameric pores (5). GSDMD pores insert themselves into the plasma membrane, allowing the deregulated passage of molecules and causing cell swelling and membrane rupture, eventually resulting in pyroptotic cell death (6).