Inflammasome activation and pyroptosis
Studies of peripheral blood and post-mortem tissues from severe COVID-19
cases reveal high levels of IL-1β and IL-6, and increased numbers of
CD14+IL-1β monocytes suggesting activation of the Nod-like receptor
family, pyrin domain-containing 3 (NLRP3) inflammasome pathway.
Activation of the NLRP3 inflammasome, essential for effective antiviral
immune responses, is elicited by several factors associated with
SARS-CoV infection including RAS disbalance, engagement of PPR, TNFR and
IFNAR, mitochondrial ROS production, complement components including
MAC, as well as SARS-CoV viral proteins such as ORF3a, N and E [figure
3, (55,85)]. As a consequence, NLRP3 interaction with adaptor
apoptosis speck-like protein (ASC) recruits and activates procaspase-1
processing pro-IL-1β, pro-IL-18 to the activate forms [figure 3].
This drives the propyroptotic factor gasdermin D (GSDMD) formation of
pores in the cell membrane, i.e. pyroptosis that facilitates the release
of proinflammatory cytokines. The pores also aid the release of cellular
DAMPS such as HMGB1, and viral PAMPS that further exacerbate
inflammation suggesting that targeting the NLRP3 pathway might be
beneficial in severe COVID-19 cases.