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

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

Research output: Contribution to journalArticle

98 Scopus citations

Abstract

Pathogenic infections and tissue injuries trigger the assembly ofinflammasomes, cytosolic protein complexes that activate caspase-1, leading to cleavage of pro-IL-10 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 synthesisof the major caspase-1 substrate pro-IL-10, the role of TLRs hasbeen considered limited to up-regulation of the inflammasomecomponents. During infection with a virulent microbe, TLRs andnucleotide-binding oligomerization domain-like receptors (NLRs)are likely activated simultaneously. To examine the requirementsand outcomes of combined activation, we stimulated TLRs anda specific NLR, nucleotide binding and oligomerization, leucine-richrepeat, pyrin domain-containing 3 (NLRP3), simultaneously anddiscovered that such activation triggers rapid caspase-1 cleavage,leading to secretion of presynthesized inflammatory moleculesand pyroptosis. This acute caspase-1 activation is independent ofnew protein synthesis and depends on the TLR-signaling moleculeIL-1 receptor-associated kinase (IRAK-1) and its kinase activity. Importantly, Listeria monocytogenes induces NLRP3-dependent rapidcaspase-1 activation and pyroptosis, both of which are compromised in IRAK-1-deficient macrophages. Our results reveal thatsimultaneous sensing of microbial ligands and virulence factorsby TLRs and NLRP3, respectively, leads to a rapid TLR- and IRAK-1 -dependent assembly of the NLRP3 inflammasome complex, andthat such activation is important for release of alarmins, pyropto-sis, and early IFN-/production by memory CD8 T cells, all of whichcould be critical for early host defense.

Original languageEnglish (US)
Pages (from-to)775-780
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number2
DOIs
Publication statusPublished - 2014

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Keywords

  • ASC
  • HMGB-1
  • Interleukin-18

ASJC Scopus subject areas

  • General

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