Reduction of streptolysin O (SLO) pore-forming activity enhances inflammasome activation.
Reduction of streptolysin O (SLO) pore-forming activity enhances inflammasome activation.
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DOI：
10.3390/toxins5061105
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发表时间：
2013-06-06
期刊：
影响因子：
4.2
通讯作者：
Salter RD
中科院分区：
文献类型：
--
作者：
Keyel PA;Roth R;Yokoyama WM;Heuser JE;Salter RD
细菌和哺乳动物细胞利用成孔毒素发挥致病作用并诱导细胞裂解。除了快速质膜修复外，巨噬细胞还通过激活NLRP 3炎性体对成孔毒素作出反应，导致IL-1β分泌和细胞凋亡。NLRP 3激活所需的成孔毒素的结构决定因素仍然未知。在这里，我们使用链球菌溶血素O（SLO）证明孔形成控制IL-1β分泌和直接毒性。不能形成孔的SLO突变体不促进直接杀伤、焦亡或IL-1β产生。这表明孔的形成是炎性小体活化所必需的。然而，与野生型SLO相比，部分活性突变体（SLO N402 C）对巨噬细胞的毒性较小，即使在直接溶解等量红细胞的浓度下，也能增强IL-1β的产生，但不会改变细胞火灾。这表明直接裂解可以通过阻止巨噬细胞成功修复其质膜并产生更稳健的细胞因子来减弱免疫应答。我们认为，致孔毒素的诱变是一种增强佐剂活性的策略。
Pore-forming toxins are utilized by bacterial and mammalian cells to exert pathogenic effects and induce cell lysis. In addition to rapid plasma membrane repair, macrophages respond to pore-forming toxins through activation of the NLRP3 inflammasome, leading to IL-1β secretion and pyroptosis. The structural determinants of pore-forming toxins required for NLRP3 activation remain unknown. Here, we demonstrate using streptolysin O (SLO) that pore-formation controls IL-1β secretion and direct toxicity. An SLO mutant incapable of pore-formation did not promote direct killing, pyroptosis or IL-1β production. This indicated that pore formation is necessary for inflammasome activation. However, a partially active mutant (SLO N402C) that was less toxic to macrophages than wild-type SLO, even at concentrations that directly lysed an equivalent number of red blood cells, enhanced IL-1β production but did not alter pyroptosis. This suggests that direct lysis may attenuate immune responses by preventing macrophages from successfully repairing their plasma membrane and elaborating more robust cytokine production. We suggest that mutagenesis of pore-forming toxins represents a strategy to enhance adjuvant activity.
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DOI：
10.1038/nri2851
发表时间：
2010-10
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
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：
32.4
作者：
Keefe, D;Shi, LF;Lieberman, J
通讯作者：
Lieberman, J
影响因子：
3.1
作者：
Limbago, B;Penumalli, V;Scott, JR
通讯作者：
Scott, JR
穿孔蛋白迅速诱导质膜磷脂触发器。
影响因子：
3.7
作者：
Metkar SS;Wang B;Catalan E;Anderluh G;Gilbert RJ;Pardo J;Froelich CJ
通讯作者：
Froelich CJ