Dexamethasone Inhibits S. aureus-Induced Neutrophil Extracellular Pathogen-Killing Mechanism, Possibly through Toll-Like Receptor Regulation.
Dexamethasone Inhibits S. aureus-Induced Neutrophil Extracellular Pathogen-Killing Mechanism, Possibly through Toll-Like Receptor Regulation.
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DOI：
10.3389/fimmu.2017.00060
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发表时间：
2017
影响因子：
7.3
通讯作者：
Jin X
中科院分区：
文献类型：
--
作者：
Wan T;Zhao Y;Fan F;Hu R;Jin X
中性粒细胞在称为 NETosis 的病原体杀灭过程中释放中性粒细胞胞外陷阱 (NET)。然而，过度的 NETs 形成与疾病发病机制有关。因此，为了了解 NETosis 是如何调节的，我们研究了抗炎药地塞米松 (DXM) 对此过程的影响以及 Toll 样受体 (TLR) 的作用。我们用佛波醇 12-肉豆蔻酸酯 13-乙酸酯 (PMA) 或金黄色葡萄球菌 (S. aureus) 刺激人类中性粒细胞，并量化 NET 的形成。我们还研究了 DXM 对 NET 杀菌作用的影响以及活性氧 (ROS) 和核因子 (NF)-κB 在 DXM 调节的 NETosis 中的作用。 DXM 显着抑制金黄色葡萄球菌诱导的 NETosis 和细胞外细菌杀灭。 ROS 产生和 NF-κB 激活不参与 DXM 调节的 NETosis。 TLR2 和 TLR4（而非 TLR5 或 TLR6）修饰了金黄色葡萄球菌诱导的 NET 形成。 DXM 和 TLR 均不参与 PMA 诱导的 NETosis。此外，TLR2和TLR4激动剂挽救了DXM抑制的NETosis，并且TLR2和TLR4拮抗剂都不能进一步抑制DXM诱导的NETosis减少，表明DXM可能通过调节TLR2和TLR4来抑制NETosis。总之，金黄色葡萄球菌和 PMA 诱导的 NETosis 的机制是不同的。 DXM 减少 NET 的形成，与氧化剂产生和 NF-κB 磷酸化无关，并且可能通过 TLR 依赖性机制。
Neutrophils release neutrophil extracellular traps (NETs) in a pathogen-killing process called NETosis. Excessive NETs formation, however, is implicated in disease pathogenesis. Therefore, to understand how NETosis is regulated, we examined the effect of dexamethasone (DXM), an anti-inflammatory drug, on this process and the role of toll-like receptors (TLRs). We stimulated human neutrophils with phorbol 12-myristate 13-acetate (PMA) or Staphylococcus aureus (S. aureus) and quantified NETs formation. We also examined the effect of DXM on the bactericidal effect of NETs and the role of reactive oxygen species (ROS) and nuclear factor (NF)-κB in DXM-regulated NETosis. DXM significantly inhibited S. aureus-induced NETosis and extracellular bacterial killing. ROS production and NF-κB activation were not involved in DXM-regulated NETosis. TLR2 and TLR4, but not TLR5 or TLR6, modified S. aureus-induced NETs formation. Neither DXM nor TLRs were involved in PMA-induced NETosis. Furthermore, TLR2 and TLR4 agonists rescued DXM-inhibited NETosis, and neither TLR2 nor TLR4 antagonists could further inhibit NETosis reduction induced by DXM, indicating that DXM may inhibit NETosis by regulating TLR2 and TLR4. In conclusion, the mechanisms of S. aureus- and PMA-induced NETosis are different. DXM decreases NETs formation independently of oxidant production and NF-κB phosphorylation and possibly via a TLR-dependent mechanism.