Projects per year
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.
|Number of pages||6|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|Early online date||30 Dec 2013|
|Publication status||Published - 14 Jan 2014|
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- 2 Finished
Elucidation of Molecular Mechanisms that Activate the MyD88 Signaling Network (Senior Investigator Award)
1/04/13 → 31/03/18