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

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.

Towards Age-Related Anti-Inflammatory Therapy: Klotho Suppresses Activation of ER and Golgi Stress Response in Senescent Monocytes

“…Although the IRE1-XBP-1 pathway is considered as being pro-survival mostly through its role in ER-associated degradation process during severe ER stress conditions, IRE1 may recruit TNF receptor-associated factor 2 and apoptosis signal-regulating kinase 1, then activate c-Jun N-terminal kinase (JNK) and induce apoptosis [20,21]. IRE-1-mediated activation of inflammasome leads to increased secretion of IL-1β and further IL-1, IL-6, and IL-8 [22]. IL-1α, as a crucial proinflammatory cytokine, has been reported to play dual function during ER stress.…”

Dihydrolipoic acid protects against lipopolysaccharide-induced behavioral deficits and neuroinflammation via regulation of Nrf2/HO-1/ NLRP3 signaling in rat

“…It is composed of NLRP3 protein, adaptor protein apoptosisrelated speckles (ASC), and procaspase-1 [43,44]. The activation of NLRP3 inflammasome triggers the transformation of procaspase-1 to caspase-1 and catalyzes the exudation of mature IL-1β and IL-18 from pro-IL-1β and pro-IL-18, causing an inflammatory response [45,46]. Previous studies showed that ROS, especially from mitochondria, activated the NLRP3 inflammasome [47,48].…”

Dihydrolipoic acid protects against lipopolysaccharide-induced behavioral deficits and neuroinflammation via regulation of Nrf2/HO-1/ NLRP3 signaling in rat

“…It is composed of NLRP3 protein, adaptor protein apoptosis-related speckles (ASC), and procaspase-1 [48,49]. The activation of NLRP3 inflammasome triggers the transformation of procaspase-1 to caspase-1 and catalyzes the exudation of mature IL-1β and IL-18 from pro-IL-1β and pro-IL-18, causing an inflammatory response [50,51]. Previous studies showed that ROS, especially from mitochondria, activated the NLRP3 inflammasome [52,53].…”