Advances in the Mechanisms Underlying the Regulation of NLRP3 Inflammasome Activation by Organelle Interaction Networks
LI Xinyu1, MAI Fengyi2,3, LIANG Jingrong2, LI Xinglong2, GUO Jie4*, LI Chenguang2*
Precise activation of the NLRP3 inflammasome serves as a pivotal hub in the regulation of host innate immune responses and the pathogenesis and progression of inflammation-related diseases. A complex cross talk network formed by organelles including mitochondria, ER (endoplasmic reticulum), Golgi apparatus, and lyso somes exerts crucial regulatory roles in this process. This review systematically summarizes the molecular mecha nisms by which various organelles participate in the regulation of NLRP3 inflammasome activation: mitochondria modulate inflammasome activity through multiple pathways such as mitochondrial membrane potential fluctuations, release of mtROS (mitochondrial reactive oxygen species), calcium overload, cardiolipin translocation, and mitoph agy; the ER provides structural and signaling support for inflammasome assembly via ER stress, calcium homeo stasis dysregulation, and signal transduction mediated by MAMs (mitochondria-associated endoplasmic reticulum membranes); the Golgi apparatus regulates the trafficking and assembly of NLRP3 inflammasome through mecha nisms including the DAG-PKD signaling axis, dTGN (dispersed trans-Golgi network)-mediated recruitment, and lipid modifications; lysosomes initiate inflammasome activation signals through cargo release induced by lysosomal membrane damage. Through dynamic interactions at membrane contact sites and precise transduction of signaling molecules, these organelles form an ordered regulatory network that collectively governs the spatial assembly and activation process of the NLRP3 inflammasome. This review provides a novel perspective for further elucidating the pathogenic mechanisms of inflammation-related diseases and lays a theoretical foundation for the development of therapeutic strategies targeting organelle interaction network.
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