Details

Autor(en) / Beteiligte

• Lin, Keng-Mean
• Hu, Wei
• Troutman, Ty Dale
• Jennings, Michelle
• Brewer, Travis
• Li, Xiaoxia
• Nanda, Sambit
• Cohen, Philip
• Thomas, James A.
• Pasare, Chandrashekhar

Titel

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

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2014-01, Vol.111 (2), p.775-780

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2014

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 monocytogene s 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.