Staphylococcal SSL5-induced platelet microparticles provoke proinflammatory responses via the CD40/TRAF6/NFκB signalling pathway in monocytes
Staphylococcal SSL5-induced platelet microparticles provoke proinflammatory responses via the CD40/TRAF6/NFκB signalling pathway in monocytes
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DOI：
10.1160/th15-04-0322
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发表时间：
2016-03-01
影响因子：
6.7
通讯作者：
Hu, Hou-Yuan
中科院分区：
文献类型：
--
作者：
Bei, Jun-Jie;Liu, Chuan;Hu, Hou-Yuan
病原体诱导的血小板活化有助于心血管疾病中的炎症，但潜在的机制仍然难以捉摸。葡萄球菌超抗原样蛋白5（SSL 5）是已知的血小板活化剂。在这里，我们检查了SSL 5是否与金黄色葡萄球菌（S.金黄色葡萄球菌）诱导的炎症和涉及的潜在机制。正如预期的那样，我们表明SSL 5激活人血小板并诱导血小板微粒（PMP）的产生。流式细胞术和扫描电子显微镜研究表明，SSL 5诱导的PMPs（SSL 5-PMPs）结合单核细胞，导致聚集体形成。此外，SSL 5-PMP以剂量和时间依赖性方式引起单核细胞表达和释放炎性介质，包括白细胞介素-1 β（IL-1 β）、肿瘤坏死因子-α（TNF α）、单核细胞趋化蛋白-1（MCP-1）和基质金属蛋白酶-9（MMP-9）。SSL 5-PMPs还增强MCP-1诱导的单核细胞迁移。阻断CD 40和CD 40配体（CD 40 L）与中和抗体的相互作用可显著减少单核细胞释放炎症介质和SSL 5-PMP诱导的迁移。siRNA介导的CD 40或TNF受体（TNFR）相关因子6（TRAF 6）基因沉默在很大程度上消除了NF κ B（p65）的磷酸化和核转位。总之，SSL 5至少部分通过PMP介导的CD 40/TRAF 6/NF κ B信号通路的激活引起单核细胞中炎症介质的释放，尽管它通常抑制白细胞功能。因此，我们的研究结果揭示了一种新的机制，S。金黄色葡萄球菌引起炎症。
Pathogens-induced platelet activation contributes to inflammation in cardiovascular diseases, but underlying mechanisms remain elusive. Staphylococcal superantigen-like protein 5 (SSL5) is a known activator of platelets. Here we examined whether SSL5 is implicated in Staphylococcus aureus (S. aureus)-induced inflammation and potential mechanisms involved. As expected, we show that SSL5 activates human platelets and induces generation of platelet microparticles (PMPs). Flow cytometry and scanning electron microscopy studies demonstrate that SSL5-induced PMPs (SSL5-PMPs) bind to monocytes, causing aggregate formation. In addition, SSL5-PMPs provoke monocyte expression and release of inflammatory mediators, including interleukin-1 beta (IL-1 beta), tumour necrosis factor-alpha (TNF alpha), monocyte chemo attractant protein-1 (MCP-1) and matrix metalloproteinase-9 (MMP-9) in a dose-and time-dependent manner. SSL5-PMPs also enhance MCP-1-induced monocyte migration. Blockade of CD40 and CD40 ligand (CD40L) interactions with neutralising antibodies significantly reduce monocyte release of inflammatory mediators and migration induced by SSL5-PMPs. SiRNA-mediated silencing of CD40 or TNF receptor (TNFR)-associated factor 6 (TRAF6) gene largely abrogates phosphorylation and nuclear translocation of NF kappa B (p65). In conclusion, SSL5 provokes the release of inflammatory mediators in monocytes, at least in part, via PMPs-mediated activation of the CD40/TRAF6/NF kappa B signalling pathway, though it normally inhibits leukocyte function. Our findings thus reveal a novel mechanism by which S. aureus induces inflammation.