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
Y1 - 2014
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 - http://www.scopus.com/inward/record.url?scp=84892610480&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84892610480&partnerID=8YFLogxK
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 -