Factor VII-Activating Protease Is Activated in Multiple Trauma Patients and Generates Anaphylatoxin C5a
Factor VII-Activating Protease Is Activated in Multiple Trauma Patients and Generates Anaphylatoxin C5a
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DOI：
10.4049/jimmunol.1103029
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发表时间：
2012-03-15
影响因子：
4.4
通讯作者：
Huber-Lang, Markus
中科院分区：
文献类型：
--
作者：
Kanse, Sandip M.;Gallenmueller, Andrea;Huber-Lang, Markus
严重的组织损伤导致丝氨酸蛋白酶系统的早期激活，包括凝血和补体级联。在这种情况下，人们对因子7活化蛋白酶（FSAP）知之甚少，它是由受损细胞释放的物质（如组蛋白和核小体）激活的。因此，我们测量了创伤患者的FSAP活性，并在人血浆中发现了新的FSAP底物。采用质谱法鉴定血浆中FSAP结合蛋白。通过ELISA、Western blotting、蛋白测序和趋化性测定测定过敏毒素的产生。分析创伤患者血浆样本的FSAP Ag及其活性、核小体、C5a和C3a。其中，我们在FSAP共免疫沉淀中发现了补体成分C3和C5。FSAP以剂量和时间依赖的方式切割C3和C5，产生功能性C3a和C5a过敏毒素。血浆中内源性FSAP的激活导致C5a的生成增加，但在FSAP活性较低的马尔堡I型单核苷酸多态性纯合携带者的血浆中并非如此。在多发创伤患者中，循环FSAP活性和核小体在损伤后立即大量增加。FSAP活性与C5a高度相关。这些数据表明，组织损伤激活FSAP会引发过敏毒素的产生，从而调节体内创伤后炎症反应。C5a、核小体和FSAP活性之间的紧密联系表明，这一新原理可能在炎症调节中很重要。免疫学杂志，2012,18(8):2858-2865。
Severe tissue injury results in early activation of serine protease systems including the coagulation and complement cascade. In this context, little is known about factor VII-activating protease (FSAP), which is activated by substances released from damaged cells such as histones and nucleosomes. Therefore, we have measured FSAP activation in trauma patients and have identified novel FSAP substrates in human plasma. Mass spectrometry-based methods were used to identify FSAP binding proteins in plasma. Anaphylatoxin generation was measured by ELISA, Western blotting, protein sequencing, and chemotaxis assays. Plasma samples from trauma patients were analyzed for FSAP Ag and activity, nucleosomes, C5a, and C3a. Among others, we found complement components C3 and C5 in FSAP coimmunoprecipitates. C3 and C5 were cleaved by FSAP in a dose- and time-dependent manner generating functional C3a and C5a anaphylatoxins. Activation of endogenous FSAP in plasma led to increased C5a generation, but this was not the case in plasma of a homozygous carrier of Marburg I single nucleotide polymorphism with lower FSAP activity. In multiple trauma patients there was a large increase in circulating FSAP activity and nucleosomes immediately after the injury. A high correlation between FSAP activity and C5a was found. These data suggest that activation of FSAP by tissue injury triggers anaphylatoxin generation and thereby modulates the posttraumatic inflammatory response in vivo. A strong link between C5a, nucleosomes, and FSAP activity indicates that this new principle might be important in the regulation of inflammation. The Journal of Immunology, 2012, 188: 2858-2865.