Inhibition of IRE1α RNase activity reduces NLRP3 inflammasome assembly and processing of pro-IL1β

TLDR

The inflammasome is a multiprotein complex activated by PAMPs and DAMPs and has become a therapeutic target for inflammatory diseases. The study investigates whether IRE1α, a key component of the unfolded protein response, contributes to NLRP3 inflammasome assembly. Inflammasome activation follows a two‑step process—priming by signal one and assembly triggered by signal two—after which the complex activates pro‑caspase‑1 to cleave pro‑IL‑18 and pro‑IL‑1β into active cytokines. Inhibition of IRE1α RNase activity reduced NLRP3 inflammasome assembly, caspase‑1 activation, and pro‑IL‑1β processing, highlighting its therapeutic potential in hyperactive inflammasome conditions.

Abstract

Abstract The inflammasome is a multiprotein complex assembled in response to Pathogen Associated Molecular Patterns (PAMPs) and Danger Associated Molecular Patterns (DAMPs). Inflammasome activation occurs through a two-step mechanism, with the first signal facilitating priming of inflammasome components while the second signal triggers complex assembly. Once assembled, the inflammasome recruits and activates pro-caspase-1, which in turn processes pro-interleukin (IL)-18 and pro-IL-1β into their bio-active forms. Owing to its key role in the regulation of innate immune responses, the inflammasome has emerged as a therapeutic target for the treatment of inflammatory conditions. In this study we demonstrate that IRE1α, a key component of the Unfolded Protein Response, contributes to assembly of the NLRP3 inflammasome. Blockade of IRE1α RNase signaling lowered NLRP3 inflammasome assembly, caspase-1 activation and pro-IL-1β processing. These results underscore both the importance and potential therapeutic relevance of targeting IRE1α signaling in conditions of excessive inflammasome formation.