Mechanism of impaired NLRP3 inflammasome priming by monophosphoryl lipid A.
Mechanism of impaired NLRP3 inflammasome priming by monophosphoryl lipid A.
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DOI：
10.1126/scisignal.2001486
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发表时间：
2011-05-03
影响因子：
7.3
通讯作者：
Mitchell TC
中科院分区：
文献类型：
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作者：
Embry CA;Franchi L;Nuñez G;Mitchell TC
单磷酰脂质A（MLA）是内毒素脂多糖（LPS）的无毒衍生物，已在美国被批准用作疫苗佐剂。LPS和MLA是Toll样受体4（TLR 4）的配体，并且一直不清楚为什么LPS触发毒性炎症，而MLA产生安全有效的免疫刺激。TLR 4下游的信号传导由衔接蛋白TRIF [含有Toll-白细胞介素-1（IL-1）受体（TIR）结构域的衔接子诱导干扰素-β]和MyD 88（髓样分化标志物88）介导，TRIF是适应性免疫结果所需的，MyD 88负责许多促炎作用。两种模型为LPS和MLA的差异效应提供了非排他性的解释。根据第一种模型，MLA不能诱导促炎细胞因子IL-1β的成熟，因为它不能激活半胱天冬酶-1，而半胱天冬酶-1是将IL-1β转化为其生物活性形式所必需的。第二个模型表明，MLA触发TLR 4的两个信号转导衔接子途径的不平等接合，使得TRIF介导的信号转导在很大程度上是完整的，而MyD 88介导的信号转导是不完整的。我们发现，TRIF偏置信号是低毒性MLA的特征，解释了其未能激活caspase-1。依赖于MyD 88的NLRP 3的诱导缺陷导致IL-1β活化炎性体的组分的组装减少，所述炎性体是活化预先形成的无活性的半胱氨酸天冬氨酸蛋白酶原-1所需的。此外，我们阐明了MyD 88和TRIF对引发NLRP 3炎性小体的贡献，并证明了MLA对TRIF偏向的TLR 4活化是导致成熟IL-1β产生缺陷的原因。
Monophosphoryl lipid A (MLA), a nontoxic derivative of the endotoxin lipopolysaccharide (LPS), has been approved in the United States for use as a vaccine adjuvant. LPS and MLA are ligands of Toll-like receptor 4 (TLR4), and it has been unclear why LPS triggers toxic inflammation, whereas MLA generates safe and effective immunostimulation. Signaling downstream of TLR4 is mediated by the adaptor proteins TRIF [Toll–interleukin-1 (IL-1) receptor (TIR) domain–containing adaptor-inducing interferon-β], which is required for adaptive immune outcomes, and MyD88 (myeloid differentiation marker 88), which is responsible for many proinflammatory effects. Two models have provided nonexclusive explanations for the differential effects of LPS and MLA. According to the first model, MLA fails to induce maturation of the proinflammatory cytokine IL-1β because it fails to activate caspase-1, which is required for the conversion of pro–IL-1β into its bioactive form. The second model suggests that MLA triggers unequal engagement of both of the signaling adaptor pathways of TLR4, such that signaling mediated by TRIF is largely intact, whereas signaling mediated by MyD88 is incomplete. We show that the TRIF-biased signaling that is characteristic of low-toxicity MLA explains its failure to activate caspase-1. Defective induction of NLRP3, which depends on MyD88, led to decreased assembly of components of the IL-1β–activating inflammasome required for the activation of preformed, inactive procaspase-1. In addition, we elucidated the contributions of MyD88 and TRIF to priming of the NLRP3 inflammasome and demonstrated that TRIF-biased TLR4 activation by MLA was responsible for the defective production of mature IL-1β.
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影响因子：
32.4
作者：
Kawai, T;Adachi, O;Akira, S
通讯作者：
Akira, S
DOI：
10.4049/jimmunol.0802367
发表时间：
2009-03-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Bryan NB;Dorfleutner A;Rojanasakul Y;Stehlik C
通讯作者：
Stehlik C
影响因子：
4.4
作者：
Li, Hanfen;Willingham, Stephen B.;Ting, Jenny P. -Y.;Re, Fabio
通讯作者：
Re, Fabio
影响因子：
56.9
作者：
Mata-Haro, Veronica;Cekic, Caglar;Mitchell, Thomas C.
通讯作者：
Mitchell, Thomas C.
链球菌为链球菌激活NLRP3炎症体需要链霉菌素O和NF-kappa B激活，但与TLR信号传导和P2X7受体无关进行。
DOI：
10.4049/jimmunol.0900444
发表时间：
2009-11-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Harder J;Franchi L;Muñoz-Planillo R;Park JH;Reimer T;Núñez G
通讯作者：
Núñez G