Extracellular vesicles, the rising stars in immunomodulation

In the past, most scholars think platelet-derived EVs are just the ashes from cells and had no idea about their functions. However, we are curious why activated platelets release so many EVs? We speculate that EVs may have holy missions during infection.

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Jun 12, 2019

At the beginning of this project, we were suffered from the spontaneous activation of platelets during sample preparation, and we are not familiar with the features and purification of extracellular vesicles (EVs). As things move on, we are excited by the magic functions of EVs from activated platelets. 

EVs are small particles released from organs/cells, and these small bubbles transduce signal or transport cargo by multiple ways- membrane-fusion, phagocytosis, endocytosis, and receptor-ligand interaction to recipients. Even though platelets were shown to enhance vascular permeability during DV infection1, but the mechanism is unclear. In this study, we found EVs from activated platelets communicate with other immune cells to enhance NET formation and proinflammatory cytokine production.

We found DV activates platelets via C-type lectin family CLEC2 to release two distinct vesicles- microvesicle and exosome, thereby activate neutrophils and macrophages via TLR2 and CLEC5A, respectively. Moreover, the CLEC2-CLEC5A/TLR2 axis does not only play a critical role in DV infection, but also in type A influenza H5N1 infection. We are surprised to find that EVs from LPS- and thrombin-activated platelets also stimulate CLEC5A/TLR2 to induce NET formation. Previously, we also showed that bacteria activate CLEC5A/TLR2 to enhance NET formation2, suggesting CLEC5A/TLR2-mediated signaling is one of the most potent pathways to induce NET formation.

We also analyze the composition of EVs by mass spectrometry, and found several candidates as ‘endogenous danger signals’, which may exist in all the EVs from activated platelets and  immune cells. Because EVs are upregulated in patients suffered from infectious and autoimmiune diseases,  we speculate that EVs may play critical roles in the pathogenesis of various human inflammatory diseases. In addition, CLEC5A/TLR2 may become the  therapeutic targets to alleviate autoimmunity in the future. This work was published in Nature Communications last week (https://www.nature.com/articles/s41467-019-10360-4)

by Pei-Shan Sung and Edmond Hsieh

1. Hottz, E. D.et al.Platelets mediate increased endothelium permeability in dengue through NLRP3-inflammasome activation. Blood122, 3405-3414, doi:10.1182/blood-2013-05-504449 (2013).

2. Chen, S. T.et al.CLEC5A is a critical receptor in innate immunity against Listeria infection. Nat Commun 8, 299, doi:10.1038/s41467-017-00356-3 (2017).

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Shie-Liang Hsieh

Distinguished Research Fellow, Academia Sinica

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