Activation of the Nlrp3 inflammasome by Streptococcus pyogenes requires streptolysin O and NF-kappa B activation but proceeds independently of TLR signaling and P2X7 receptor.
Activation of the Nlrp3 inflammasome by Streptococcus pyogenes requires streptolysin O and NF-kappa B activation but proceeds independently of TLR signaling and P2X7 receptor.
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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
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发表时间：
2009-11-01
期刊：
影响因子：
--
通讯作者：
Núñez G
中科院分区：
文献类型：
--
作者：
Harder J;Franchi L;Muñoz-Planillo R;Park JH;Reimer T;Núñez G
巨噬细胞在针对人类病原体化脓性链球菌的先天免疫应答中起关键作用，然而针对细菌的先天免疫应答的特征很差。在本研究中，我们发现，caspase-1激活和IL-1β分泌诱导活的，而不是杀死S。化脓性链球菌，并需要孔形成毒素链球菌溶血素O的表达。使用缺乏炎性体成分的巨噬细胞，我们发现Nlrp 3和Asc在响应S.化脓性感染相反，缺乏必需TLR衔接子Myd 88和Trif的巨噬细胞显示半胱天冬酶-1的正常激活，但对pro-IL-1β的诱导和IL-1β的分泌受损。值得注意的是，TLR 2和TLR 4配体在SLO存在下激活caspase-1需要Myd 88/Trif，而S.通过抑制NF-κB阻断化脓性链球菌。与TLR配体激活Nlrp 3炎性小体不同，S.化脓性链球菌不需要外源性ATP或P2 X7 R。体内实验表明，Nlrp 3对IL-1β的产生至关重要，但对S.化脓性腹膜感染这些结果表明，响应于S.化脓性链球菌感染需要NF-κB和毒力因子链球菌溶血素O，但不依赖于P2 X7 R和TLR信号传导。
Macrophages play a crucial role in the innate immune response against the human pathogen Streptococcus pyogenes, yet the innate immune response against the bacterium is poorly characterized. In the present study, we show that caspase-1 activation and IL-1β secretion were induced by live, but not killed S. pyogenes, and required expression of the pore-forming toxin streptolysin O. Using macrophages deficient in inflammasome components, we found that both Nlrp3 and Asc were crucial for caspase-1 activation and IL-1β secretion, but dispensable for pro-IL-1β induction, in response to S. pyogenes infection. Conversely, macrophages deficient in the essential TLR adaptors Myd88 and Trif showed normal activation of caspase-1, but impaired induction of pro-IL-1β and secretion of IL-1β. Notably, activation of caspase-1 by TLR2 and TLR4 ligands in the presence of SLO required Myd88/Trif whereas that induced by S. pyogenes was blocked by inhibition of NF-κB. Unlike activation of the Nlrp3 inflammasome by TLR ligands, the induction of caspase-1 activation by S. pyogenes did not require exogenous ATP or the P2X7R. In vivo experiments revealed that Nlrp3 was critical for the production of IL-1β but was not important for survival in a mouse model of S. pyogenes peritoneal infection. These results indicate that caspase-1 activation in response to S. pyogenes infection requires NF-κB and the virulence factor streptolysin O, but proceeds independently of P2X7R and TLR signaling.
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