The NLRP3 inflammasome at the crossroads of innate immune signaling and cell death.

Abstract

The NLRP3 inflammasome is a central signaling pathway of innate immunity that orchestrates host defense and inflammatory responses through the activation of proinflammatory cytokines and the induction of pyroptotic cell death. Accumulating evidence indicates that NLRP3 functions within an extensive network of innate immune and cell death pathways. Reciprocal interactions between NLRP3 and other pattern-recognition receptor pathways, including Toll-like receptors, DNA-sensing cGAS-STING signaling, and RNA-sensing RIG-I/MDA5-MAVS signaling, shape the magnitude and duration of inflammatory responses during pathogen infection. Moreover, substantial crosstalk exists between NLRP3 and other inflammasomes and programmed cell death pathways, reflecting the integrated nature of cellular stress and inflammatory signaling. In this review, we summarize recent advances in our understanding of the molecular mechanisms that mediate these interactions, focusing on shared signaling components, organelle dynamics, posttranslational modifications, and feedback regulatory circuits. We further discuss how these signaling networks contribute to infectious and inflammatory diseases and highlight key unanswered questions and emerging areas of investigation that may guide the development of therapies targeting inflammasome-associated pathologies.