The Canonical Inflammasome: A Macromolecular Complex Driving Inflammation

Abstract

The inflammasome is a multi-molecular platform crucial to the induction of an inflammatory response to cellular danger. Recognition in the cytoplasm of endogenously and exogenously derived ligands initiates conformational change in sensor proteins, such as NLRP3, that permits the subsequent rapid recruitment of adaptor proteins, like ASC, and the resulting assembly of a large-scale inflammatory signalling platform. The assembly process is driven by sensor-sensor interactions as well as sensor-adaptor and adaptor-adaptor interactions. The resulting complex, which can reach diameters of around 1 micron, has a variable composition and stoichiometry. The inflammasome complex functions as a platform for the proximity induced activation of effector caspases, such as caspase-1 and caspase-8. This ultimately leads to the processing of the inflammatory cytokines pro-IL1β and pro-IL18 into their active forms, along with the cleavage of Gasdermin D, a key activator of cell death via pyroptosis.

Keywords: AIM2; ASC; Caspase; Cell death; Death domain; IL-1beta; Inflammasome; Inflammation; Innate immunity; Interleukin; NLR; Pyroptosis; Supramolecular-organising centre.