FADD and caspase-8 mediate priming and activation of the canonical and noncanonical Nlrp3 inflammasomes.
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.
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105;
Prajwal
P
Gurung
Paras K
PK
Anand
R K Subbarao
RK
Malireddi
Lieselotte
L
Vande Walle
Nina
N
Van Opdenbosch
Christopher P
CP
Dillon
Ricardo
R
Weinlich
Douglas R
DR
Green
Mohamed
M
Lamkanfi
Thirumala-Devi
TD
Kanneganti
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000276:immunology*; D020170:Caspase 1 / Q000378:metabolism; D053181:Caspase 8 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D053471:Caspases, Initiator; D044082:Citrobacter rodentium / Q000276:immunology; D004756:Enterobacteriaceae Infections / Q000276:immunology; D004789:Enzyme Activation; D053200:Fas-Associated Death Domain Protein / Q000235:genetics / Q000378:metabolism*; D058847:Inflammasomes / Q000276:immunology*; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides; D008264:Macrophages / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics; D014158:Transcription, Genetic
D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D058847:Inflammasomes; D053583:Interleukin-1beta; C512299:Ipaf protein, mouse; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; C101136:Casp4 protein, mouse; D053181:Caspase 8; D020169:Caspases; D053471:Caspases, Initiator; D020170:Caspase 1