IRAK-1 bypasses priming and directly links TLRs to rapid NLRP3 inflammasome activation
IRAK-1 bypasses priming and directly links TLRs to rapid NLRP3 inflammasome activation
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DOI：
10.1073/pnas.1320294111
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发表时间：
2014-01-14
影响因子：
11.1
通讯作者：
Pasare, Chandrashekhar
中科院分区：
文献类型：
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作者：
Lin, Keng-Mean;Hu, Wei;Pasare, Chandrashekhar
病原性感染和组织损伤触发炎性体的组装，炎性体是激活半胱天冬酶-1的胞质蛋白复合物，导致pro-IL-1 β和pro-IL-18的裂解和焦亡，一种促炎性细胞死亡程序。尽管已知Toll样受体（TLR）的微生物识别诱导主要半胱天冬酶-1底物pro-IL-1 β的合成，但认为TLR的作用仅限于炎性体组分的上调。在用毒性微生物感染期间，TLR和核苷酸结合寡聚化结构域样受体（NLR）可能同时被激活。为了检查联合激活的要求和结果，我们同时刺激TLR和特定的NLR、核苷酸结合和寡聚化、富含亮氨酸的重复序列、含pyrin结构域3（NLRP 3），并发现这种激活触发快速caspase-1裂解，导致合成前炎症分子的分泌和细胞凋亡。这种急性半胱天冬酶-1激活不依赖于新蛋白质的合成，并依赖于TLR信号分子IL-1受体相关激酶（IRAK-1）及其激酶活性。重要的是，单核细胞增生李斯特菌诱导NLRP 3依赖性快速半胱天冬酶-1活化和焦亡，这两者在IRAK-1缺陷型巨噬细胞中受到损害。我们的研究结果表明，同时感测微生物配体和毒力因子的TLR和NLRP 3，分别导致一个快速的TLR和IRAK 1依赖组装的NLRP 3炎性体复合物，这种激活是重要的释放alarmins，pyroptosis，和早期IFN-γ生产的记忆CD 8 T细胞，所有这些都可能是至关重要的早期宿主防御。
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.