Extracellular vesicles from CLEC2-activated platelets enhance dengue virus-induced lethality via CLEC5A/TLR2

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Abstract

Platelet-leukocyte interactions amplify inflammatory reactions, but the underlying mechanism is still unclear. CLEC5A and CLEC2 are spleen tyrosine kinase (Syk)-coupled C-type lectin receptors, abundantly expressed by leukocytes and platelets, respectively. Whereas CLEC5A is a pattern recognition receptor (PRR) to flaviviruses and bacteria, CLEC2 is the receptor for platelet-activating snake venom aggretin. Here we show that dengue virus (DV) activates platelets via CLEC2 to release extracellular vesicles (EVs), including exosomes (EXOs) and microvesicles (MVs). DV-induced EXOs (DV-EXOs) and MVs (DV-MVs) further activate CLEC5A and TLR2 on neutrophils and macrophages, thereby induce neutrophil extracellular trap (NET) formation and proinflammatory cytokine release. Compared to stat1 ^−/− mice, simultaneous blockade of CLEC5A and TLR2 effectively attenuates DV-induced inflammatory response and increases survival rate from 30 to 90%. The identification of critical roles of CLEC2 and CLEC5A/TLR2 in platelet-leukocyte interactions will support the development of novel strategies to treat acute viral infection in the future.

Abstract

Dengue virus (DENV) promotes leukocyte-platelet interactions that contribute to pathogenesis. Here, the authors report a role for C-type lectins CLEC2 and CLEC5A in platelet activation and NET formation and show that blockade of CLEC5A and TLR2 attenuates inflammation and increases survival of infected mice.

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Most cited references 30

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Excessive Neutrophils and Neutrophil Extracellular Traps Contribute to Acute Lung Injury of Influenza Pneumonitis

Teluguakula Narasaraju, Edwin Yang, Ramar Samy … (2011)

Complications of acute respiratory distress syndrome (ARDS) are common among critically ill patients infected with highly pathogenic influenza viruses. Macrophages and neutrophils constitute the majority of cells recruited into infected lungs, and are associated with immunopathology in influenza pneumonia. We examined pathological manifestations in models of macrophage- or neutrophil-depleted mice challenged with sublethal doses of influenza A virus H1N1 strain PR8. Infected mice depleted of macrophages displayed excessive neutrophilic infiltration, alveolar damage, and increased viral load, later progressing into ARDS-like pathological signs with diffuse alveolar damage, pulmonary edema, hemorrhage, and hypoxemia. In contrast, neutrophil-depleted animals showed mild pathology in lungs. The brochoalveolar lavage fluid of infected macrophage-depleted mice exhibited elevated protein content, T1-α, thrombomodulin, matrix metalloproteinase-9, and myeloperoxidase activities indicating augmented alveolar-capillary damage, compared to neutrophil-depleted animals. We provide evidence for the formation of neutrophil extracellular traps (NETs), entangled with alveoli in areas of tissue injury, suggesting their potential link with lung damage. When co-incubated with infected alveolar epithelial cells in vitro, neutrophils from infected lungs strongly induced NETs generation, and augmented endothelial damage. NETs induction was abrogated by anti-myeloperoxidase antibody and an inhibitor of superoxide dismutase, thus implying that NETs generation is induced by redox enzymes in influenza pneumonia. These findings support the pathogenic effects of excessive neutrophils in acute lung injury of influenza pneumonia by instigating alveolar-capillary damage.

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Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4.

Alexzander Asea, Michael Rehli, Edith Kabingu … (2002)

Recent studies have initiated a paradigm shift in the understanding of the function of heat shock proteins (HSP). It is now clear that HSP can and do exit mammalian cells, interact with cells of the immune system, and exert immunoregulatory effects. We recently demonstrated that exogenously added HSP70 possesses potent cytokine activity, with the ability to bind with high affinity to the plasma membrane, elicit a rapid intracellular Ca(2+) flux, activate NF-kappaB, and up-regulate the expression of pro-inflammatory cytokines in human monocytes. Here for the first time, we report that HSP70-induced proinflammatory cytokine production is mediated via the MyD88/IRAK/NF-kappaB signal transduction pathway and that HSP70 utilizes both TLR2 (receptor for Gram-positive bacteria) and TLR4 (receptor for Gram-negative bacteria) to transduce its proinflammatory signal in a CD14-dependent fashion. These studies now pave the way for the development of highly effective pharmacological or molecular tools that will either up-regulate or suppress HSP70-induced functions in conditions where HSP70 effects are desirable (cancer) or disorders where HSP70 effects are undesirable (arthritis and arteriosclerosis).

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Neutrophil extracellular traps mediate a host defense response to human immunodeficiency virus-1.

Tatsuya Saitoh, Jun A. Komano, Yasunori Saitoh … (2012)

Neutrophils contribute to pathogen clearance by producing neutrophil extracellular traps (NETs), which are genomic DNA-based net-like structures that capture bacteria and fungi. Although NETs also express antiviral factors, such as myeloperoxidase and α-defensin, the involvement of NETs in antiviral responses remains unclear. We show that NETs capture human immunodeficiency virus (HIV)-1 and promote HIV-1 elimination through myeloperoxidase and α-defensin. Neutrophils detect HIV-1 by Toll-like receptors (TLRs) TLR7 and TLR8, which recognize viral nucleic acids. Engagement of TLR7 and TLR8 induces the generation of reactive oxygen species that trigger NET formation, leading to NET-dependent HIV-1 elimination. However, HIV-1 counteracts this response by inducing C-type lectin CD209-dependent production of interleukin (IL)-10 by dendritic cells to inhibit NET formation. IL-10 suppresses the reactive oxygen species-dependent generation of NETs induced upon TLR7 and TLR8 engagement, resulting in disrupted NET-dependent HIV-1 elimination. Therefore, NET formation is an antiviral response that is counteracted by HIV-1. Copyright © 2012 Elsevier Inc. All rights reserved.

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Author and article information

Contributors

Shie-Liang Hsieh:

ORCID: http://orcid.org/0000-0001-9415-346X

slhsieh@gate.sinica.edu.tw

Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-1723

Publication date (Electronic): 3 June 2019

Publication date PMC-release: 3 June 2019

Publication date Collection: 2019

Volume: 10

Electronic Location Identifier: 2402

Affiliations

[1 ]ISNI 0000 0001 0425 5914, GRID grid.260770.4, Institute of Clinical Medicine, , National Yang-Ming University, ; 11221, Taipei, Taiwan

[2 ]ISNI 0000 0004 1762 5613, GRID grid.452449.a, Department of Medicine, , Mackay Medical College, ; 25245, New Taipei City, Taiwan

[3 ]ISNI 0000 0004 0546 0241, GRID grid.19188.39, Department of Pharmacology, College of Medicine, , National Taiwan University, ; 10051, Taipei, Taiwan

[4 ]ISNI 0000 0001 2287 1366, GRID grid.28665.3f, Genomics Research Center, , Academia Sinica, ; Taipei, 11529 Taiwan

[5 ]ISNI 0000 0004 0604 5314, GRID grid.278247.c, Department of Medical Research, , Taipei Veterans General Hospital, ; 11217, Taipei, Taiwan

Author information

Pei-Shan Sung http://orcid.org/0000-0002-5061-4989

Shie-Liang Hsieh http://orcid.org/0000-0001-9415-346X

Article

Publisher ID: 10360

DOI: 10.1038/s41467-019-10360-4

PMC ID: 6546763

PubMed ID: 31160588

SO-VID: 81447c0e-31b3-41d0-888c-4888b2d6af28

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 15 October 2018

Date accepted : 8 May 2019

Funding

Funded by: FundRef https://doi.org/10.13039/501100001869, Academia Sinica;

Award ID: 107-2101-01-18-03

Award ID: AS-TP-106-L11

Award ID: AS-TP-106-L11-1

Award Recipient : Shie-Liang Hsieh

Funded by: FundRef https://doi.org/10.13039/501100004663, Ministry of Science and Technology, Taiwan (Ministry of Science and Technology of Taiwan);

Award ID: MOST 107-2321-B-001-015

Award ID: MOST 106-2320-B-001-023-MY3

Award Recipient : Shie-Liang Hsieh

Funded by: VGH, TSGH, AS Joint Research Program (VTA107-V2-1-2)

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ScienceOpen disciplines: Uncategorized

Keywords: infection,infectious diseases,inflammation,innate immune cells,innate immunity

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ScienceOpen disciplines: Uncategorized

Keywords: infection, infectious diseases, inflammation, innate immune cells, innate immunity

Extracellular vesicles from CLEC2-activated platelets enhance dengue virus-induced lethality via CLEC5A/TLR2

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Bacterial extracellular vesicles

Most cited references 30

Excessive Neutrophils and Neutrophil Extracellular Traps Contribute to Acute Lung Injury of Influenza Pneumonitis

Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4.

Neutrophil extracellular traps mediate a host defense response to human immunodeficiency virus-1.

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