Fig. 3.

Upregulation of hepatocyte inflammasome signalling in cirrhosis predisposes to exacerbated cell death following SARS-CoV-2 infection. In cirrhosis (right panel) bacterial products (such as lipopolysaccharide) bind and activate Caspases-4/5 leading to cleavage of the dimeric protein Gasdermin-D (GSDMD). GSDMD N-terminal migrates to the plasma membrane, forming pores that allow the unregulated passage of damage-associated molecular patterns and electrolytes. K⁺ efflux and mitochondrial damage are also triggers of NLRP3 assembly, which in turns activates caspase-1 and leads to processing of pro-IL1β. Upon SARS-Cov-2 infection, viral proteins react with the already assembled NLRP3, leading to activation of downstream pathways. By contrast, in healthy liver (left panel), absence of ACE2 receptor delays the entry of SARS-CoV-2 into the cells. NLRP3 is present, but inactive, thus slowing the progress towards activation of pro-inflammatory caspases and processing of GSDMD and pro-IL1β