Complement C5a Induces Pro-inflammatory Microvesicle Shedding in Severely Injured Patients
Complement C5a Induces Pro-inflammatory Microvesicle Shedding in Severely Injured Patients
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DOI：
10.3389/fimmu.2020.01789
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发表时间：
2020-09-02
影响因子：
7.3
通讯作者：
Halbgebauer, Rebecca
中科院分区：
文献类型：
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作者：
Karasu, Ebru;Demmelmaier, Julia;Halbgebauer, Rebecca
最初被低估为血小板粉尘的细胞外小泡在炎症领域不断受到关注。各种针对炎症性疾病的研究表明，源自不同细胞类型的微囊泡(MVS)是一种全身运输工具，携带不同的货物来调节免疫反应。在本研究中，我们重点研究了多发伤的临床背景，其特征是天然免疫的液体相和细胞成分的激活和功能障碍。考虑到中性粒细胞对补体过敏性毒素C5a的敏感性，我们假设C5a的产生增加导致中性粒细胞MV脱落的改变，从而导致中性粒细胞功能障碍，从而加剧创伤后炎症。在一项对多重创伤患者进行的单中心前瞻性临床研究中，我们发现其表面含有C5a受体(C5aR1，CD88)的粒细胞来源的MVs显著增加。这一发现伴随着粒细胞上C5aR1的伴随丢失，表明细胞趋化和促炎中性粒细胞功能受损。此外，在体外暴露于人中性粒细胞(来自健康志愿者)时，C5a显著增加了中性粒细胞上MV的脱落和C5aR1的丢失，这可以被C5aR1拮抗剂PMX53所阻断。机制分析表明，C5aR1信号与小GTP酶Arf6之间的相互作用是MV脱落的分子开关。当中性粒细胞来源时，C5a诱导的MV暴露在复杂的活体全血模型中，MVS的显著促炎特性(NADPH活性、ROS和MPO产生)变得明显。C5a诱导的MVS激活静息中性粒细胞，并显著刺激IL-6的分泌。这些数据提示了C5a-C5aR1轴的一个新的作用：C5a诱导的中性粒细胞MV脱落一方面导致C5aR1表面表达减少，另一方面导致深刻的炎症信号，这可能是中性粒细胞功能障碍的关键驱动因素，这在多发创伤患者中经常被观察到。
Initially underestimated as platelet dust, extracellular vesicles are continuously gaining interest in the field of inflammation. Various studies addressing inflammatory diseases have shown that microvesicles (MVs) originating from different cell types are systemic transport vehicles carrying distinct cargoes to modulate immune responses. In this study, we focused on the clinical setting of multiple trauma, which is characterized by activation and dysfunction of both, the fluid-phase and the cellular component of innate immunity. Given the sensitivity of neutrophils for the complement anaphylatoxin C5a, we hypothesized that increased C5a production induces alterations in MV shedding of neutrophils resulting in neutrophil dysfunction that fuels posttraumatic inflammation. In a mono-centered prospective clinical study with polytraumatized patients, we found significantly increased granulocyte-derived MVs containing the C5a receptor (C5aR1, CD88) on their surface. This finding was accompanied by a concomitant loss of C5aR1 on granulocytes indicative of an impaired cellular chemotactic and pro-inflammatory neutrophil functions. Furthermore,in vitroexposure of human neutrophils (from healthy volunteers) to C5a significantly increased MV shedding and C5aR1 loss on neutrophils, which could be blocked using the C5aR1 antagonist PMX53. Mechanistic analyses revealed that the interaction between C5aR1 signaling and the small GTPase Arf6 acts as a molecular switch for MV shedding. When neutrophil derived, C5a-induced MV were exposed to a complexex vivowhole blood model significant pro-inflammatory properties (NADPH activity, ROS and MPO generation) of the MVs became evident. C5a-induced MVs activated resting neutrophils and significantly induced IL-6 secretion. These data suggest a novel role of the C5a-C5aR1 axis: C5a-induced MV shedding from neutrophils results in decreased C5aR1 surface expression on the one hand, on the other hand it leads to profound inflammatory signals which likely are both key drivers of the neutrophil dysfunction which is regularly observed in patients suffering from multiple traumatic injuries.