Abstract
The Nlrp3 inflammasome is critical for host immunity, but the mechanisms controlling its activation are enigmatic. In this study, we show that loss of FADD or caspase-8 in a RIP3-deficient background, but not RIP3 deficiency alone, hampered transcriptional priming and posttranslational activation of the canonical and noncanonical Nlrp3 inflammasome. Deletion of caspase-8 in the presence or absence of RIP3 inhibited caspase-1 and caspase-11 activation by Nlrp3 stimuli but not the Nlrc4 inflammasome. In addition, FADD deletion prevented caspase-8 maturation, positioning FADD upstream of caspase-8. Consequently, FADD- and caspase-8-deficient mice had impaired IL-1β production when challenged with LPS or infected with the enteropathogen Citrobacter rodentium. Thus, our results reveal FADD and caspase-8 as apical mediators of canonical and noncanonical Nlrp3 inflammasome priming and activation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis Regulatory Proteins / metabolism
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Calcium-Binding Proteins / metabolism
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Carrier Proteins / immunology*
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Caspase 1 / metabolism
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Caspase 8 / genetics
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Caspase 8 / immunology
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Caspase 8 / metabolism*
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Caspases / metabolism
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Caspases, Initiator
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Citrobacter rodentium / immunology
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Enterobacteriaceae Infections / immunology
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Enzyme Activation
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Fas-Associated Death Domain Protein / genetics
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Fas-Associated Death Domain Protein / metabolism*
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Inflammasomes / immunology*
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Interleukin-1beta / metabolism
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Lipopolysaccharides
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Macrophages / immunology
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Mice
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Mice, Knockout
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NLR Family, Pyrin Domain-Containing 3 Protein
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Receptor-Interacting Protein Serine-Threonine Kinases / deficiency
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Receptor-Interacting Protein Serine-Threonine Kinases / genetics
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Transcription, Genetic
Substances
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Apoptosis Regulatory Proteins
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Calcium-Binding Proteins
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Carrier Proteins
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Fadd protein, mouse
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Fas-Associated Death Domain Protein
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Inflammasomes
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Interleukin-1beta
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Ipaf protein, mouse
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Lipopolysaccharides
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NLR Family, Pyrin Domain-Containing 3 Protein
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Nlrp3 protein, mouse
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Receptor-Interacting Protein Serine-Threonine Kinases
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Ripk3 protein, mouse
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Casp4 protein, mouse
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Caspase 8
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Caspases
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Caspases, Initiator
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Caspase 1