Division of Infection Medicine, Department of Clinical Sciences, Faculty of Medicine, Lund University, Lund, Sweden.
J Innate Immun. 2018;10(1):30-43. doi: 10.1159/000480386. Epub 2017 Oct 17.
The formation of neutrophil extracellular traps (NETs) is a host defence mechanism, known to facilitate the entrapment and growth inhibition of many bacterial pathogens. It has been implicated that the translocation of myeloperoxidase (MPO) from neutrophilic granules to the nucleus is crucial to this process. Under disease conditions, however, excessive NET formation can trigger self-destructive complications by releasing pathologic levels of danger-associated molecular pattern molecules (DAMPs). To counteract such devastating immune reactions, the host has to rely on precautions that help circumvent these deleterious effects. Though the induction of DAMP responses has been intensively studied, the mechanisms that are used by the host to down-regulate them are still not understood. In this study, we show that p33 is an endothelial-derived protein that has the ability to annul NET formation. We found that the expression of human p33 is up-regulated in endothelial cells upon infections with Streptococcus pyogenes bacteria. Using tissue biopsies from a patient with streptococcal necrotising fasciitis, we monitored co-localisation of p33 with MPO. Further in vitro studies revealed that p33 is able to block the formation of DAMP-induced NET formation by inhibiting the enzymatic activity of MPO. Additionally, mice challenged with S. pyogenes bacteria demonstrated diminished MPO activity when treated with p33. Together, our results demonstrate that host-derived p33 has an important immunomodulating function that helps to counterbalance an overwhelming DAMP response.
中性粒细胞胞外诱捕网（NETs）的形成是一种宿主防御机制，已知它可以帮助捕获和抑制许多细菌病原体的生长。已有研究表明，髓过氧化物酶（MPO）从中性粒细胞颗粒向细胞核的易位对这一过程至关重要。然而，在疾病状态下，过多的 NET 形成会通过释放病理性水平的危险相关分子模式分子（DAMPs）引发自我破坏的并发症。为了对抗这种破坏性的免疫反应，宿主必须依靠一些预防措施来避免这些有害影响。尽管 DAMP 反应的诱导已经得到了深入研究，但宿主用来下调它们的机制仍未被理解。在这项研究中，我们表明 p33 是一种内皮细胞衍生的蛋白，它具有抑制 NET 形成的能力。我们发现，人 p33 的表达在感染化脓性链球菌后在内皮细胞中上调。使用来自患有链球菌坏死性筋膜炎的患者的组织活检，我们监测了 p33 与 MPO 的共定位。进一步的体外研究表明，p33 能够通过抑制 MPO 的酶活性来阻止 DAMPs 诱导的 NET 形成。此外，用 p33 处理感染化脓性链球菌的小鼠，其 MPO 活性降低。总之，我们的研究结果表明，宿主来源的 p33 具有重要的免疫调节功能，可以帮助平衡压倒性的 DAMP 反应。
