title: IRAK-1 bypasses priming and directly links TLRs to rapid NLRP3 inflammasome activation.
abstract: Pathogenic infections and tissue injuries trigger the assembly of inflammasomes, cytosolic protein complexes that activate caspase-1, leading to cleavage of pro-IL-1β and pro-IL-18 and to pyroptosis, a proinflammatory cell death program. Although microbial recognition by Toll-like receptors (TLRs) is known to induce the synthesis of the major caspase-1 substrate pro-IL-1β, the role of TLRs has been considered limited to up-regulation of the inflammasome components. During infection with a virulent microbe, TLRs and nucleotide-binding oligomerization domain-like receptors (NLRs) are likely activated simultaneously. To examine the requirements and outcomes of combined activation, we stimulated TLRs and a specific NLR, nucleotide binding and oligomerization, leucine-rich repeat, pyrin domain-containing 3 (NLRP3), simultaneously and discovered that such activation triggers rapid caspase-1 cleavage, leading to secretion of presynthesized inflammatory molecules and pyroptosis. This acute caspase-1 activation is independent of new protein synthesis and depends on the TLR-signaling molecule IL-1 receptor-associated kinase (IRAK-1) and its kinase activity. Importantly, Listeria monocytogenes induces NLRP3-dependent rapid caspase-1 activation and pyroptosis, both of which are compromised in IRAK-1-deficient macrophages. Our results reveal that simultaneous sensing of microbial ligands and virulence factors by TLRs and NLRP3, respectively, leads to a rapid TLR- and IRAK-1-dependent assembly of the NLRP3 inflammasome complex, and that such activation is important for release of alarmins, pyroptosis, and early IFN-γ production by memory CD8 T cells, all of which could be critical for early host defense.
authors.affiliation: Departments of Pediatrics and Immunology, University of Texas Southwestern Medical Center, Dallas TX 75390.
authors.forename: Keng-Mean
authors.initials: KM
authors.lastname: Lin
authors.forename: Wei
authors.initials: W
authors.lastname: Hu
authors.forename: Ty Dale
authors.initials: TD
authors.lastname: Troutman
authors.forename: Michelle
authors.initials: M
authors.lastname: Jennings
authors.forename: Travis
authors.initials: T
authors.lastname: Brewer
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
authors.forename: Sambit
authors.initials: S
authors.lastname: Nanda
authors.forename: Philip
authors.initials: P
authors.lastname: Cohen
authors.forename: James A
authors.initials: JA
authors.lastname: Thomas
authors.forename: Chandrashekhar
authors.initials: C
authors.lastname: Pasare
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000276:immunology*; D020170:Caspase 1 / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D004789:Enzyme Activation / Q000276:immunology*; D047468:Immunoprecipitation; D058847:Inflammasomes / Q000276:immunology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism*; D008264:Macrophages; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D051193:Toll-Like Receptors / Q000276:immunology*
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D051193:Toll-Like Receptors; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse; D020170:Caspase 1
keywords: ASC; HMGB-1; Interleukin-18