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

Bali LeeChristopher HoyleRose WellensJack P GreenFatima Martin-SanchezDaniel M WilliamsBillie J MatchettPaula I SeoaneHayley BennettAntony D AdamsonGloria Lopez-CastejonMartin LoweDavid Brough
Published in: Science signaling (2023)
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.
Keyphrases
  • nlrp inflammasome
  • signaling pathway
  • oxidative stress
  • electronic health record
  • big data
  • resting state
  • cancer therapy
  • cell proliferation
  • pi k akt
  • artificial intelligence