Properdin homeostasis requires turnover of the alternative complement pathway.
Properdin homeostasis requires turnover of the alternative complement pathway.
复制标题
备解素稳态需要补体旁路途径的更新。
DOI：
10.1073/pnas.1006608107
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发表时间：
2010
影响因子：
11.1
通讯作者：
Atkinson,JohnP
中科院分区：
文献类型：
--
作者：
Wu,Xiaobo;Xu,ThomasQ;Atkinson,JohnP
备解素是一种血浆蛋白，在刺激后也从嗜中性粒细胞颗粒释放。在炎症部位，它可以结合细菌和凋亡小体，触发旁路途径（AP）激活。控制备解素体内平衡的原理尚不清楚。我们监测备解素在AP激活和补体缺陷小鼠。在Crry单敲除小鼠（Crry SKO）中备解素减少>90%。这些膜补体调节蛋白缺陷小鼠的特征是AP周转加快，导致C3和fB减少。将眼镜蛇毒因子注射到野生型小鼠中激活AP，并导致C3，fB和备解素的消耗。然而，出乎意料的是，备解素在C3 −/−、fB−/−和fD −/−小鼠中也有缺陷。它存在于C1 q −/−、C4−/−和C5 −/−小鼠中。这些发现暗示AP周转在维持血液中备解素的基础水平。为了探索机制，输注经典途径激活免疫复合物。在10分钟内，备解素在B −/−小鼠中部分恢复，但在C3 −/−小鼠中没有。在缺乏AP组分的小鼠中备解素的显著减少及其通过激活C3的部分恢复表明需要通过AP tickover持续激活C3以维持备解素稳态。这种C3依赖性过程的机制尚未确定。排除了C3 a和C5 a受体的结合。这些发现代表了先天免疫识别和效应途径的正调节因子是如何控制的一个有指导意义的例子。提出了一种为免疫反应提供备解素的方法。
Properdin is a plasma protein and is also released from neutrophil granules following stimulation. At inflammatory sites it can bind bacteria and apoptotic bodies to trigger alternative pathway (AP) activation. Principles governing properdin homeostasis are unknown. We monitored properdin during AP activation and in complement-deficient mice. There was a >90% reduction of properdin in the Crry single-knockout mice (Crry SKO). These membrane complement regulatory protein-deficient mice feature accelerated AP turnover, leading to reduced C3 and fB. Injecting cobra venom factor into wild-type mice activated the AP and led to the consumption of C3, fB, and properdin. However, and unexpectedly, properdin was also deficient inC3−/−,fB−/−, andfD−/−mice. It was present inC1q−/−,C4−/−, andC5−/−mice. These findings implicate AP turnover in the maintenance of basal levels of properdin in the blood. To explore the mechanism, classical pathway-activating immune complexes were infused. Within 10 min, properdin was partially restored infB−/−but not inC3−/−mice. Markedly reduced properdin in mice deficient in an AP component and its partial restoration by activating C3 suggest a requirement for continuous C3 activation via AP tickover to maintain properdin homeostasis. The mechanism underlying this C3-dependent process was not identified. Engagement of C3a and C5a receptors was ruled out. These findings represent an instructive example of how a positive regulator of an innate immune recognition and effector pathway is controlled. A rationale for such a means to supply properdin for immune reactions is proposed.