FIG. 2.

Models of NLRP3 inflammasome activation. Considered to be a two-step mechanism, the primary signal comes from the activation of toll-like receptors (TLRs) and is responsible for the upregulation of NLRP3 and pro-interleukin-1β (IL-1β) in an NF-kappaB (NF-κB)-dependent manner. Secondary signals come from multiple pathways: K⁺ efflux via P2X7 receptor activation, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, NADPH oxidase, frustrated phagocytosis, and lysosomal rupture pathways, all of which appear to converge in the production of reactive oxygen species (ROS). Together, these primary and secondary signals activate the NLRP3 inflammasome, resulting in proteolytic cleavage of caspase-1 and the maturation of IL-1β. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars