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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-1? 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-1?, 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-? production by memory CD8 T cells, all of which could be critical for early host defense.

SUBMITTER: Lin KM

PROVIDER: S-EPMC3896167 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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IRAK-1 bypasses priming and directly links TLRs to rapid NLRP3 inflammasome activation.

Lin Keng-Mean KM Hu Wei W Troutman Ty Dale TD Jennings Michelle M Brewer Travis T Li Xiaoxia X Nanda Sambit S Cohen Philip P Thomas James A JA Pasare Chandrashekhar C

Proceedings of the National Academy of Sciences of the United States of America 20131230 2

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 virule ...[more]

PMID: 24379360

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Dataset Information

IRAK-1 bypasses priming and directly links TLRs to rapid NLRP3 inflammasome activation.

Publications

IRAK-1 bypasses priming and directly links TLRs to rapid NLRP3 inflammasome activation.

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