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.
Highlights
Platelet-leukocyte interactions amplify inflammatory reactions, but the underlying mechanism is still unclear
We show that dengue virus (DV) activates platelets via CLEC2, causing them to release extracellular vesicles (EVs) that further enhance neutrophil extracellular trap (NET) formation and proinflammatory cytokine production through activation of CLEC5A and toll-like receptor 2 (TLR2) on macrophages and neutrophils
Because EVs released from DV-activated platelets (DV-EVs) play critical roles in homeostasis and disease[19,20], we asked whether DV-EVs contribute to platelet-mediated enhancement of
Summary
Platelet-leukocyte interactions amplify inflammatory reactions, but the underlying mechanism is still unclear. DV infection has been shown to activate macrophages and platelets to secrete proinflammatory cytokines and extracellular vesicles (EVs)[6,7,8,9]; the most severe responses to DV are systemic inflammation and increased vascular permeability. GlcNAc-MurNAc disaccharides of bacterial peptidoglycans, and is co-activated with toll-like receptor 2 (TLR2) by Listeria monocytogenes and Staphylococcus aureus, thereby inducing NET formation and proinflammatory cytokine release[14]. This observation indicates that CLEC5A works closely with TLR2 in pathogen-induced inflammatory reactions
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