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

TY - JOUR

T1 - IRAK-1 bypasses priming and directly links TLRs torapid NLRP3 inflammasome activation

AU - Lin, Keng Mean

AU - Hu, Wei

AU - Troutman, T. Dale

AU - Jennings, Michelle

AU - Brewer, Travis

AU - Li, Xiaoxia

AU - Nanda, Sambit

AU - Cohen, Philip

AU - Thomas, James A.

AU - Pasare, Chandrashekhar

PY - 2014/1/14

Y1 - 2014/1/14

N2 - 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.

AB - 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.

KW - ASC

KW - HMGB-1

KW - Interleukin-18

UR - https://www.scopus.com/pages/publications/84892610480

U2 - 10.1073/pnas.1320294111

DO - 10.1073/pnas.1320294111

M3 - Article

C2 - 24379360

AN - SCOPUS:84892610480

SN - 0027-8424

VL - 111

SP - 775

EP - 780

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 2

ER -