Figure 1

Model of NLRP3 inflammasome activation. NLRP3 is activated by a vast array of stimuli including extracellular pathogen PAMPs such as bacterial LPS via pattern recognition receptors (PRR) such as Toll-like receptors (TLR) and DAMPs. This comprises signal 1 and leads to synthesis of the cytokine precursor pro-IL-1β via NF-κB and other components of the inflammasome such as NLRP3 itself. Many of the known activators of the inflammasome generate ROS which can bind to NLRP3 and this appears necessary for its activation. Extracellular ATP binding to the P2X7 receptor (P2X7R) comprises signal 2. This promotes the recruitment and opening of the pannexin-1 pore channel which causes rapid K⁺ efflux, another event which appears necessary for NLRP3 activation. NLRP3 assembly occurs when, through its pyrin domain, NLRP3 binds to the pyrin domain on an ASC molecule which then binds to pro-caspase-1 via its CARD domain. This leads to cleavage of pro-caspase-1 and subsequent cleavage of pro-IL-1β and pro-IL-18 to their active forms. Abbreviations: DAMP, damage-associated molecular pattern; LPS, lipopolysaccharide; ROS, reactive oxygen species; PAMP, pathogen-associated molecular pattern; PRR, pattern recognition receptor; TLR, toll-like receptor; PYD, pyrin domain.