NLRP1-dependent pyroptosis leads to acute lung injury and morbidity in mice.
NLRP1-dependent pyroptosis leads to acute lung injury and morbidity in mice.
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DOI：
10.4049/jimmunol.1201065
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发表时间：
2012-08-15
期刊：
影响因子：
--
通讯作者：
Koller BH
中科院分区：
文献类型：
--
作者：
Kovarova M;Hesker PR;Jania L;Nguyen M;Snouwaert JN;Xiang Z;Lommatzsch SE;Huang MT;Ting JP;Koller BH
响应外源性和内源性危险信号的急性炎症可导致细胞质炎症小体的组装，从而刺激 caspase-1 的激活。随后，caspase-1 促进细胞因子的成熟和释放，并且在某些情况下还促进细胞焦亡诱导细胞死亡。使用缺乏 NLRP1 表达的小鼠系，我们发现细胞中这种炎症小体的组装是由炭疽毒素触发的，并且它启动 caspase-1 激活和 IL-1β 的释放。此外，NLRP1 炎性体激活还会导致细胞死亡，细胞死亡在接触毒素后三天内不断升级，最终导致小鼠急性肺损伤和死亡。我们发现这些事件并不依赖于炎症小体产生 IL-1β，而是依赖于 caspase-1 的表达。相反，MDP 介导的炎症小体形成不依赖于 NLRP1，而是依赖于 NLRP3。综上所述，我们的研究结果表明，NLRP1炎性小体的组装足以引发细胞焦亡，随后导致肺内细胞损伤的自我放大级联反应，而肺无法从中恢复，最终对生物体造成灾难性后果。
Acute inflammation in response to both exogenous and endogenous danger signals can lead to the assembly of cytoplasmic inflammasomes that stimulate the activation of caspase-1. Subsequently, caspase-1 facilitates the maturation and release of cytokines and also, under some circumstances, the induction of cell death by pyroptosis. Using a mouse line lacking expression of NLRP1, we show that assembly of this inflammasome in cells is triggered by a toxin from Anthrax and that it initiates caspase-1 activation and release of IL-1β. Furthermore, NLRP1 inflammasome activation also leads to cell death, which escalates over three days following exposure to the toxin and culminates in acute lung injury and death of the mice. We show that these events are not dependent on production of IL-1β by the inflammasome but are dependent on caspase-1 expression. In contrast, MDP mediated inflammasome formation is not dependent on NLRP1, but NLRP3. Taken together, our findings show that assembly of the NLRP1 inflammasome is sufficient to initiate pyroptosis, which subsequently leads to a self-amplifying cascade of cell injury within the lung from which the lung cannot recover, eventually resulting in catastrophic consequences for the organism.
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DOI：
10.4049/jimmunol.1003111
发表时间：
2011-02-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Davis BK;Roberts RA;Huang MT;Willingham SB;Conti BJ;Brickey WJ;Barker BR;Kwan M;Taxman DJ;Accavitti-Loper MA;Duncan JA;Ting JP
通讯作者：
Ting JP
影响因子：
16
作者：
Martinon, F;Burns, K;Tschopp, J
通讯作者：
Tschopp, J
影响因子：
30.5
作者：
Franchi, Luigi;Amer, Amal;Nunez, Gabriel
通讯作者：
Nunez, Gabriel
影响因子：
32.4
作者：
Khare S;Dorfleutner A;Bryan NB;Yun C;Radian AD;de Almeida L;Rojanasakul Y;Stehlik C
通讯作者：
Stehlik C
影响因子：
6.7
作者：
Levinsohn JL;Newman ZL;Hellmich KA;Fattah R;Getz MA;Liu S;Sastalla I;Leppla SH;Moayeri M
通讯作者：
Moayeri M