Staphylococcus aureus Panton-Valentine leukocidin induces an inflammatory response in human phagocytes via the NLRP3 inflammasome
Staphylococcus aureus Panton-Valentine leukocidin induces an inflammatory response in human phagocytes via the NLRP3 inflammasome
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DOI：
10.1189/jlb.0112014
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发表时间：
2012-11-01
影响因子：
5.5
通讯作者：
Loeffler, Bettina
中科院分区：
文献类型：
--
作者：
Holzinger, Dirk;Gieldon, Laura;Loeffler, Bettina
金黄色葡萄球菌致孔毒素PVL最有可能导致危及生命的坏死性感染，其特征是大量组织炎症和坏死。虽然PVL对人中性粒细胞的细胞毒性作用已经得到了很好的证实，但PVL对其他敏感细胞类型，如单核细胞和巨噬细胞的影响还不是很清楚。在这项研究中，我们使用不同类型的人白细胞(中性粒细胞、单核细胞、巨噬细胞、淋巴细胞)来研究PVL亚单位的细胞特异性结合以及随后的促炎和细胞毒效应。在所有PVL敏感细胞中，我们发现LuKS-PV亚基的结合是PVL诱导细胞毒性的关键因素，其次是LukF-PV的结合。Luks-PV与单核细胞、巨噬细胞和中性粒细胞结合，但不与淋巴细胞结合。此外，我们还发现PVL与单核细胞和巨噬细胞结合导致caspase-1依赖的促炎细胞因子IL-1β和IL-18的释放。PVL激活NLRP3炎症体，这是一种髓系细胞的信号复合体，参与caspase-1依赖的IL-1β处理，以响应病原体和内源性危险信号。在几个步骤中对该途径的特异性抑制显著减少了炎性小体的激活和随后的肾小球坏死。此外，我们发现来自垂死的中性粒细胞的PAMP和DAMP可以通过上调单核/巨噬细胞中的前IL-1β来显著增强这种反应。本研究分析了一条介导PVL诱导的炎症和细胞毒性的特定宿主信号通路，该通路与CA-MRSA相关和PVL介导的致病过程(如坏死性感染)具有很高的相关性。J.Leukoc。比奥尔。92：1069-1081；2012。
The Staphylococcus aureus pore-forming toxin PVL is most likely causative for life-threatening necrotizing infections, which are characterized by massive tissue inflammation and necrosis. Whereas the cytotoxic action of PVL on human neutrophils is already well established, the PVL effects on other sensitive cell types, such as monocytes and macrophages, are less clear. In this study, we used different types of human leukocytes (neutrophils, monocytes, macrophages, lymphocytes) to investigate cell-specific binding of PVL subunits and subsequent proinflammatory and cytotoxic effects. In all PVL-sensitive cells, we identified the binding of the subunit LukS-PV as the critical factor for PVL-induced cytotoxicity, which was followed by binding of LukF-PV. LukS-PV binds to monocytes, macrophages, and neutrophils but not to lymphocytes. Additionally, we showed that PVL binding to monocytes and macrophages leads to release of caspase-1-dependent proinflammatory cytokines IL-1 beta and IL-18. PVL activates the NLRP3 inflammasome, a signaling complex of myeloid cells that is involved in caspase-1-dependent IL-1 beta processing in response to pathogens and endogenous danger signals. Specific inhibition of this pathway at several steps significantly reduced inflammasome activation and subsequent pyronecrosis. Furthermore, we found that PAMPs and DAMPs derived from dying neutrophils can dramatically enhance this response by up-regulating pro-IL-1 beta in monocytes/macrophages. This study analyzes a specific host signaling pathway that mediates PVL-induced inflammation and cytotoxicity, which has high relevance for CA-MRSA-associated and PVL-mediated pathogenic processes, such as necrotizing infections. J. Leukoc. Biol. 92: 1069-1081;2012.