Figure 2.

The two signaling arms of the inflammasome-activation cascade.

Notes: Signal 1 pathways sense environmental signals via surface Tumor necrosis factor (TNF), Toll-like (TLR) and IL-1 receptors and facilitates transcriptional priming of inflammasome components via the NFκB pathway and upregulates the expression of precursor proteins of IL1β, caspases 1/11(also known as caspase 4), and pro-Nod-like receptors (NLR). Signal 2 facilitates activation of the complex via proteolytic processing and assembly. This arm responds to mechanical stress, activation of a ligand-sensing system within the cytosol or extracellular ATP sensing via Panx1–P2X receptor signalosomes. Upon activation, protease activity of caspases regulates the maturation and release of IL1β and IL18. Recent studies showed that Gasdermin D (GSDMD) is a novel membrane pore-forming protein. Cleaved by inflammatory caspases Casp1 or Casp11(4), GSDMD binds to phosphoinositides in the plasma membrane and oligomerizes to generate membrane pores of ~10–14 nm in diameter.²²² This pore size can allow the passage of mature IL1β, IL18, and caspase 1. The formation of the GSDMD pores also disrupts osmotic potential, resulting in an inflammatory form of cell death known as pyroptosis.

Abbreviation: ASC, apoptosis-associate speck-like protein containing a caspase recruitment domain.