Disruptions in endocytic traffic contribute to the activation of the NLRP3 inflammasome.

Inflammation driven by the NLRP3 inflammasome is coordinated through multiple signaling pathways and is regulated by subcellular organelles. Here, we tested the hypothesis that NLRP3 senses disrupted endosome trafficking to trigger inflammasome formation and inflammatory cytokine secretion. NLRP3-activating stimuli disrupted endosome trafficking and triggered localization of NLRP3 to vesicles positive for endolysosomal markers and for the inositol lipid PI4P. Chemical disruption of endosome trafficking sensitized macrophages to the NLRP3 activator imiquimod, driving enhanced inflammasome activation and cytokine secretion. Together, these data suggest that NLRP3 can sense disruptions in the trafficking of endosomal cargoes, which may explain in part the spatial activation of the NLRP3 inflammasome. These data highlight mechanisms that could be exploited in the therapeutic targeting of NLRP3. Inflammation-inducing traffic jams: The NLRP3 inflammasome assembles and is activated by diverse cellular stresses to produce proinflammatory cytokines. Lee et al. investigated whether the NLRP3 inflammasome was activated by disruptions in endosomal trafficking. By analyzing various cell types, including bone marrow-derived macrophages, the authors found that NLRP3-activating stimuli resulted in perturbations in endosomal trafficking and conversely, that chemical interference with endosomal trafficking potentiated NLRP3 activation, although it was insufficient to activate NLRP3 by itself. Activated NLRP3 was recruited to endolysosomal vesicles, where it colocalized with the lipid PI4P, which the authors speculated may be the additional stimulus required for NLRP3 activation. Thus, NLRP3 senses and is activated by cellular stress resulting from disordered endosomal trafficking. —WW [ABSTRACT FROM AUTHOR]