TLR agonists stimulate Nlrp3-dependent IL-1β production independently of the purinergic P2X7 receptor in dendritic cells and in vivo.
TLR agonists stimulate Nlrp3-dependent IL-1β production independently of the purinergic P2X7 receptor in dendritic cells and in vivo.
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DOI：
10.4049/jimmunol.1202737
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发表时间：
2013-01-01
期刊：
影响因子：
--
通讯作者：
Núñez G
中科院分区：
文献类型：
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作者：
He Y;Franchi L;Núñez G
基于对小鼠巨噬细胞的研究，Nlrp3炎性体的激活被认为需要两个信号。第一个信号由toll样受体刺激提供，并触发IL-1β前体和Nlrp3的合成。第二种信号可以通过毫摩尔浓度的ATP刺激嘌呤能P2X7受体介导。然而，这些高浓度的ATP在体内细胞外环境中通常不存在，这引起了人们对ATP- p2x7途径与炎性小体激活的生理相关性的关注。在这里，我们发现，与巨噬细胞不同，小鼠骨髓源性和脾dc在没有ATP刺激的情况下，在TLR配体刺激下可以分泌大量成熟的IL-1β。DCs释放IL-1β和激活caspase-1的能力差异与稳态条件下Nlrp3的表达增加以及TLR激动剂刺激后pro-IL-1β和Nlrp3的表达增加有关。受刺激的dc分泌IL-1β在很大程度上依赖于Nlrp3炎性体，但不依赖于P2X7，不受apyrase孵育的影响。更重要的是，腹腔注射LPS诱导血清中IL-1β的产生，在nlrp3缺失的小鼠中被消除，而在p2x7缺失的小鼠中则不受影响。这些结果表明Nlrp3炎性体在巨噬细胞和树突状细胞中的调节存在差异。此外，他们挑战了ATP-P2X7轴对tlr诱导的IL-1β通过Nlrp3炎性体在体内产生至关重要的观点。
Activation of the Nlrp3 inflammasome has been proposed to require two signals based on studies in mouse macrophages. The first signal is provided by Toll-like receptor stimulation and triggers the synthesis of the IL-1β precursor and Nlrp3. The second signal can be mediated by stimulation of the purinergic P2X7 receptor by millimolar concentrations of ATP. However, these high concentrations of ATP are not found normally in the in vivo extracellular milieu, raising concern about the physiological relevance of the ATP-P2X7 pathway of inflammasome activation. Here, we show that unlike macrophages, murine bone marrow derived and splenic DCs can secrete substantial amounts of mature IL-1β upon stimulation with TLR ligands in the absence of ATP stimulation. The differential ability of DCs to release IL-1β and activate caspase-1 was associated with increased expression of Nlrp3 under steady state conditions and of pro-IL-1β and Nlrp3 after stimulation with TLR agonists. IL-1β secretion from stimulated DCs was largely dependent on the Nlrp3 inflammasome, but independent of P2X7 and unaffected by incubation with apyrase. More importantly, intraperitoneal administration of LPS induced IL-1β production in serum which was abrogated in Nlrp3-null mice but was unaffected in P2X7-deficient mice. These results demonstrate differential regulation of the Nlrp3 inflammasome in macrophages and dendritic cells. Furthermore, they challenge the notion that the ATP-P2X7 axis is critical for TLR-induced IL-1β production via the Nlrp3 inflammasome in vivo.
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影响因子：
32.4
作者：
Sutterwala, FS;Ogura, Y;Flavell, RA
通讯作者：
Flavell, RA
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：
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作者：
Harder J;Franchi L;Muñoz-Planillo R;Park JH;Reimer T;Núñez G
通讯作者：
Núñez G
DOI：
10.1073/pnas.0709684105
发表时间：
2008-06-10
影响因子：
11.1
作者：
Piccini, Alessandra;Carta, Sonia;Rubartelli, Anna
通讯作者：
Rubartelli, Anna
影响因子：
4.4
作者：
Beigi, RD;Dubyak, GR
通讯作者：
Dubyak, GR
影响因子：
30.5
作者：
通讯作者：
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