| Summary: | 博士 === 國立陽明大學 === 臨床醫學研究所 === 107 === Activated-platelet acts as an enhancer of inflammation, however, how activated-platelet communicates with other cells to promote inflammatory reaction is still unclear. CLEC5A and CLEC2 are spleen tyrosine kinase-coupled C-type lectin receptors (Syk-CLRs) abundantly expressed in leukocytes and platelets, respectively. While CLEC5A is the pattern recognition receptor responsible for bacteria- and flaviviruses-induced inflammatory responses in macrophages and neutrophils, CLEC2 is the receptor for snake venom aggretin in platelet. Here we report that dengue virus (DV) activates platelets via CLEC2 to release extracellular vesicles (EVs, including microvesicles/MVs and exosomes/EXOs). 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. Anti-TLR2 mAb reduces DV-induced NET formation and proinflammatory cytokines in both stat1-/- and stat1-/-clec5a-/- mice significantly in vivo, and further protects stat1-/-clec5a-/- mice from DV-induced lethality. Our observations suggest that CLEC2 and CLEC5A/TLR2 play critical role in platelet-leukocyte interactions, and simultaneous blockade of CLEC5A/TLR2 might become a novel strategy for the treatment of acute viral infection in the future.
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