Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 2, Pages 775-780Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1320294111
Keywords
Interleukin-18; ASC; HMGB-1
Categories
Funding
- National Institutes of Health [AI082265, P50 GM021681]
- Welch Foundation [I-1820]
- Kaminski Family Foundation
- Medical Research Council [MC_EX_UU_G0800765, MR/K000985/1, MC_U127084348, MC_EX_G0800765, MC_UU_12016/11] Funding Source: researchfish
- MRC [MC_EX_UU_G0800765, MR/K000985/1, MC_U127084348, MC_UU_12016/11, MC_EX_G0800765] Funding Source: UKRI
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Pathogenic infections and tissue injuries trigger the assembly of inflammasomes, cytosolic protein complexes that activate caspase-1, leading to cleavage of pro-IL-1 beta 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-1 beta, 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 monocytogenes 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 IRAK1-dependent assembly of the NLRP3 inflammasome complex, and that such activation is important for release of alarmins, pyroptosis, and early IFN-gamma production by memory CD8 T cells, all of which could be critical for early host defense.
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