Microbial pathogen-induced necrosis mediated by NLRP3 and ASC Public Deposited

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  • March 21, 2019
  • Willingham, Stephen B.
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
  • NLRP3 and ASC are important components of the inflammasome, a multi-protein complex required for caspase-1 activation and IL-1[beta] production. NLRP3 mutations underlie autoinflammation characterized by excessive IL-1[beta] secretion. Disease-associated NLRP3 also causes a program of necrosis-like cell death in macrophages, the mechanistic details of which are unknown. We find that patient monocytes carrying disease-associated NLRP3 mutations exhibit excessive necrosis-like cell death by a process dependent on ASC and cathepsin B, resulting in spillage of the proinflammatory mediator HMGB1. Shigella flexneri and Klebsiella pneumoniae infection also cause NLRP3-dependent macrophage necrosis with features similar to the death caused by mutant NLRP3. This necrotic death is independent of caspase-1 and IL-1[beta], and thus independent of the inflammasome. While similar proteins mediate pathogen-induced cell death in plants, this report identifies NLRP3 as an important host regulator of pathogen-induced necrosis in animals, a process we term pyronecrosis.
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  • In Copyright
  • Ting, Jenny P.-Y.
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  • University of North Carolina at Chapel Hill
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