Figure 2

Damage-associated molecular patterns and the NLRP3 inflammasome. The NLRP3 inflammasome is a multiprotein complex with an important role in the production of mature IL-1β and IL-18. Activation of NF-κB - for example, via Toll-like receptor (TLR) signaling - is necessary for the production of pro-IL-1β and pro-IL-18 (signal 1). Pathogen-derived factors as well as damage-associated molecular patterns (DAMPs) - including uric acid, ATP, biglycan, and hyaluronan (HA) - can activate NLRP3 (signal 2). How these various stimuli activate NLRP3 is not completely elucidated. Three intracellular features are associated with NLRP3 activation: (a) potassium efflux, (b) increased reactive oxygen species (ROS) levels, and (c) lysosomal damage and the release of cathepsin B. Catabolism of HA leads to the release of small oligosaccharide fragments. How these fragments exactly activate NLRP3 is unclear. Activated NLRP3 assembles with adaptor protein apoptosis-associated speck-like protein (ASC) and pro-caspase-1 to form active caspase-1, which cleaves pro-IL-1β and pro-IL-18 into their mature form. MyD88, myeloid-differentiation primary response protein 88.