Critical roles of ASC inflammasomes in caspase-1 activation and host innate resistance to Streptococcus pneumoniae infection.
Critical roles of ASC inflammasomes in caspase-1 activation and host innate resistance to Streptococcus pneumoniae infection.
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DOI：
10.4049/jimmunol.1100381
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发表时间：
2011-11-01
期刊：
影响因子：
--
通讯作者：
Mitsuyama M
中科院分区：
文献类型：
--
作者：
Fang R;Tsuchiya K;Kawamura I;Shen Y;Hara H;Sakai S;Yamamoto T;Fernandes-Alnemri T;Yang R;Hernandez-Cuellar E;Dewamitta SR;Xu Y;Qu H;Alnemri ES;Mitsuyama M
肺炎链球菌是一种革兰氏阳性的胞外细菌，在全球范围内导致大量死亡和发病率。肺炎球菌溶血素(Ply)是肺炎球菌临床分离株产生的一种溶细胞素，是该病原体最重要的毒力因子之一。我们以前曾报道，在感染肺炎链球菌的巨噬细胞中，PLY是激活caspase-1并随后分泌IL-1β和IL-18的一个必不可少的因素。然而，参与caspase-1激活的宿主分子因素仍不清楚。为了进一步阐明感染肺炎链球菌的巨噬细胞中caspase-1激活的机制，我们研究了炎症小体在诱导这种细胞反应中的参与。我们的研究发现，含有caspase募集结构域(ASC)的凋亡相关斑点样蛋白(ASC)是肺炎链霉菌诱导caspase-1激活所必需的。ASC是炎症体受体的适配蛋白，如NLR家族，PYRIN结构域包含3(NLRP3)，在黑色素瘤中缺失(AIM2)。NLRP3−/−巨噬细胞的caspase-1活性部分受损，而AIM2基因的敲除和敲除则导致肺炎链球菌对caspase-1活性的明显降低。这些结果表明，包括AIM2和NLRP3在内的ASC炎性小体在肺炎链球菌诱导的caspase-1激活中起关键作用。此外，Asc−/−小鼠比野生型小鼠更容易感染肺炎链球菌，鼻腔感染后IL-1β和IL-18分泌到支气管肺泡灌洗液中的能力下降，提示Asc炎症体有助于保护宿主免受产层肺炎链球菌的感染。
Streptococcus pneumoniae is a Gram-positive, extracellular bacterium that is responsible for significant mortality and morbidity worldwide. Pneumolysin (PLY), a cytolysin produced by all clinical isolates of the pneumococcus, is one of the most important virulence factors of this pathogen. We have previously reported that PLY is an essential factor for activation of caspase-1 and consequent secretion of IL-1β and IL-18 in macrophages infected with S. pneumoniae. However, the host molecular factors involved in caspase-1 activation are still unclear. To further elucidate the mechanism of caspase-1 activation in macrophages infected with S. pneumoniae, we examined the involvement of inflammasomes in inducing this cellular response. Our study revealed that apoptosis-associated speck like protein containing a caspase recruitment domain (ASC), an adaptor protein for inflammasome receptors such as NLR family, pyrin domain containing 3 (NLRP3) and absent in melanoma 2 (AIM2), is essentially required for the induction of caspase-1 activation by S. pneumoniae. Caspase-1 activation was partially impaired in NLRP3−/− macrophages, while knockdown and knockout of AIM2 resulted in a clear decrease in caspase-1 activation in response to S. pneumoniae. These results suggest that ASC inflammasomes, including AIM2 and NLRP3, are critical for caspase-1 activation induced by S. pneumoniae. Furthermore, ASC−/− mice were more susceptible than wild-type mice to S. pneumoniae, with impaired secretion of IL-1β and IL-18 into the bronchoalveolar lavage after intranasal infection, suggesting that ASC inflammasomes contribute to the protection of host from infection with PLY-producing S. pneumoniae.
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影响因子：
30.5
作者：
Buerckstuemmer, Tilmann;Baumann, Christoph;Superti-Furga, Giulio
通讯作者：
Superti-Furga, Giulio
影响因子：
30.5
作者：
Franchi, Luigi;Amer, Amal;Nunez, Gabriel
通讯作者：
Nunez, Gabriel
影响因子：
4.4
作者：
Kafka, Daniel;Ling, Eduard;Mizrachi-Nebenzahl, Yaffa
通讯作者：
Mizrachi-Nebenzahl, Yaffa
影响因子：
30.5
作者：
通讯作者：
--
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