Distinct changes in endosomal composition promote NLRP3 inflammasome activation

Inflammasome complexes are pivotal in the innate immune response. The NLR family pyrin domain containing protein 3 (NLRP3) inflammasome is activated in response to a broad variety of cellular stressors. However, a primary and converging sensing mechanism by the NLRP3 receptor initiating inflammasome assembly remains ill defined. Here, we demonstrate that NLRP3 inflammasome activators primarily converge on disruption of endoplasmic reticulum-endosome membrane contact sites (EECS). This defect causes endosomal accumulation of phosphatidylinositol 4-phosphate (PI4P) and a consequent impairment of endosome-to-trans-Golgi network trafficking (ETT), necessary steps for endosomal recruitment of NLRP3 and subsequent inflammasome activation. Lowering endosomal PI4P levels prevents endosomal association of NLRP3 and inhibits inflammasome activation. Disruption of EECS or ETT is sufficient to enhance endosomal PI4P levels, to recruit NLRP3 to endosomes and to potentiate NLRP3 inflammasome activation. Mice with defects in ETT in the myeloid compartment are more susceptible to lipopolysaccharide-induced sepsis. Our study thus identifies a distinct cellular mechanism leading to endosomal NLRP3 recruitment and inflammasome activation. A dogma in the inflammasome field is that NLRP3 activation occurs at dispersed vesicles of the trans-Golgi network. Here, Ricci and colleagues find that these vesicles are of endosomal origin and that endosomes comprise the compartment where NLRP3 is activated.

Automated summary

The NLRP3 inflammasome plays a crucial role in the innate immune response, and disruption of the endoplasmic reticulum-endosome membrane contact sites (EECS) leads to NLRP3 accumulation in endosomes and activation of the inflammasome. Lowering endosomal phosphatidylinositol 4-phosphate (PI4P) levels prevents NLRP3 association with endosomes and inhibits inflammasome activation. This discovery helps us better understand the activation mechanism of the inflammasome.