Granulocyte-Derived Extracellular Vesicles Activate Monocytes and Are Associated With Mortality in Intensive Care Unit Patients.
Granulocyte-Derived Extracellular Vesicles Activate Monocytes and Are Associated With Mortality in Intensive Care Unit Patients.
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DOI：
10.3389/fimmu.2018.00956
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发表时间：
2018
影响因子：
7.3
通讯作者：
Norris PJ
中科院分区：
文献类型：
--
作者：
Danesh A;Inglis HC;Abdel-Mohsen M;Deng X;Adelman A;Schechtman KB;Heitman JW;Vilardi R;Shah A;Keating SM;Cohen MJ;Jacobs ES;Pillai SK;Lacroix J;Spinella PC;Norris PJ
为了理解细胞外囊泡（EV）亚型如何差异地激活单核细胞，进行了一系列体外研究。我们发现血浆EV使单核细胞偏向M1分布。培养单核细胞与粒细胞，单核细胞，和内皮-EV诱导几种促炎细胞因子。相比之下，血小板-EV诱导TGF-β和GM-CSF，并且红细胞（RBC）-EV在体外不激活单核细胞。清道夫受体CD 36对于RBC-EV与单核细胞的结合是重要的，而阻断CD 36、CD 163、CD 206、TLR 1、TLR 2和TLR 4在体外不影响血浆-EV与单核细胞的结合。为了确定死亡危险因素，在重症监护病房入院时测量患者血浆中的多种可溶性因子和EV亚型。在测定的43种凝血因子和细胞因子中，有两种与死亡率显著相关，即组织型纤溶酶原激活物和胱抑素C。在EV上定量的14种细胞标志物中，4种是死亡率的早期预测因子，包括粒细胞标志物CD 66 b。总之，粒细胞EV在体外对单核细胞具有有效的促炎作用。此外，早期粒细胞EV水平与危重病患者死亡率的相关性为干预与危重病相关的促炎级联反应提供了一个潜在的靶点。
To understand how extracellular vesicle (EV) subtypes differentially activate monocytes, a series of in vitro studies were performed. We found that plasma-EVs biased monocytes toward an M1 profile. Culturing monocytes with granulocyte-, monocyte-, and endothelial-EVs induced several pro-inflammatory cytokines. By contrast, platelet-EVs induced TGF-β and GM-CSF, and red blood cell (RBC)-EVs did not activate monocytes in vitro. The scavenger receptor CD36 was important for binding of RBC-EVs to monocytes, while blockade of CD36, CD163, CD206, TLR1, TLR2, and TLR4 did not affect binding of plasma-EVs to monocytes in vitro. To identify mortality risk factors, multiple soluble factors and EV subtypes were measured in patients’ plasma at intensive care unit admission. Of 43 coagulation factors and cytokines measured, two were significantly associated with mortality, tissue plasminogen activator and cystatin C. Of 14 cellular markers quantified on EVs, 4 were early predictors of mortality, including the granulocyte marker CD66b. In conclusion, granulocyte-EVs have potent pro-inflammatory effects on monocytes in vitro. Furthermore, correlation of early granulocyte-EV levels with mortality in critically ill patients provides a potential target for intervention in management of the pro-inflammatory cascade associated with critical illness.