Changes and Regulation of the C5a Receptor on Neutrophils during Septic Shock in Humans
Changes and Regulation of the C5a Receptor on Neutrophils during Septic Shock in Humans
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DOI：
10.4049/jimmunol.1200534
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发表时间：
2013-04-15
影响因子：
4.4
通讯作者：
Huber-Lang, Markus
中科院分区：
文献类型：
--
作者：
Unnewehr, Heike;Rittirsch, Daniel;Huber-Lang, Markus
在实验性脓毒症期间，过敏毒素C5 a的过量产生导致中性粒细胞上的C5 a受体（C5 aR）减少。这些事件已被证明会导致先天免疫力受损。然而，在脓毒症期间中性粒细胞上的C5 aR的调节和命运在很大程度上是未知的。与30名健康志愿者相比，60名感染性休克患者存在补体激活的证据，血清C3 a、C5 a和C5 b-9水平显著升高。在感染性休克组中，补体溶血活性的相应降低区分了幸存者和非幸存者。感染性休克患者的中性粒细胞C5 aR表达降低，与血清C反应蛋白（CRP）浓度和临床结局呈负相关。在体外暴露的正常中性粒细胞的天然五聚体CRP导致剂量和时间依赖性的损失C5 aR表达的中性粒细胞，而单体形式的CRP，以及各种其他炎症介质，未能显着改变中性粒细胞上的C5 aR水平。通过免疫印迹和基于流动的捕获试验在血清中检测到循环形式的C5 aR（cC 5aR），提示完整的C5 aR分子。cC 5aR水平在感染性休克期间显著增强，血清水平与致死率直接相关。这些数据表明，人类感染性休克与广泛的补体激活、中性粒细胞上C5 aR的CRP依赖性丢失和血清中cC 5aR的出现相关，这与不良结局相关。因此，cC 5aR可能代表一种新的脓毒症标志物，可用于定制个性化免疫调节治疗。免疫学杂志，2013，190：4215-4225。
During experimental sepsis, excessive generation of the anaphylatoxin C5a results in reduction of the C5a receptor (C5aR) on neutrophils. These events have been shown to result in impaired innate immunity. However, the regulation and fate of C5aR on neutrophils during sepsis are largely unknown. In contrast to 30 healthy volunteers, 60 patients in septic shock presented evidence of complement activation with significantly increased serum levels of C3a, C5a, and C5b-9. In the septic shock group, the corresponding decrease in complement hemolytic activity distinguished survivors from nonsurvivors. Neutrophils from patients in septic shock exhibited decreased C5aR expression, which inversely correlated with serum concentrations of C-reactive protein (CRP) and clinical outcome. In vitro exposure of normal neutrophils to native pentameric CRP led to a dose- and time-dependent loss of C5aR expression on neutrophils, whereas the monomeric form of CRP, as well as various other inflammatory mediators, failed to significantly alter C5aR levels on neutrophils. A circulating form of C5aR (cC5aR) was detected in serum by immunoblotting and a flow-based capture assay, suggestive of an intact C5aR molecule. Levels of cC5aR were significantly enhanced during septic shock, with serum levels directly correlating with lethality. The data suggest that septic shock in humans is associated with extensive complement activation, CRP-dependent loss of C5aR on neutrophils, and appearance of cC5aR in serum, which correlated with a poor outcome. Therefore, cC5aR may represent a new sepsis marker to be considered in tailoring individualized immune-modulating therapy. The Journal of Immunology, 2013, 190: 4215-4225.