Institute of Clinical Medicine, National Yang-Ming University, 11221, Taipei, Taiwan.
Department of Medicine, Mackay Medical College, 25245, New Taipei City, Taiwan.
Nat Commun. 2019 Jun 3;10(1):2402. doi: 10.1038/s41467-019-10360-4.
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.
血小板-白细胞相互作用可放大炎症反应，但潜在机制尚不清楚。CLEC5A 和 CLEC2 分别是脾脏酪氨酸激酶（Syk）偶联的 C 型凝集素受体，在白细胞和血小板中大量表达。虽然 CLEC5A 是一种模式识别受体（PRR），可识别黄病毒和细菌，但 CLEC2 是血小板激活蛇毒聚集素的受体。在这里，我们表明登革热病毒（DV）通过 CLEC2 激活血小板释放细胞外囊泡（EVs），包括外泌体（EXOs）和微泡（MVs）。DV 诱导的 EXOs（DV-EXOs）和 MVs（DV-MVs）进一步激活中性粒细胞和巨噬细胞上的 CLEC5A 和 TLR2，从而诱导中性粒细胞胞外诱捕网（NET）形成和促炎细胞因子释放。与 stat1 小鼠相比，同时阻断 CLEC5A 和 TLR2 可有效减轻 DV 诱导的炎症反应，将存活率从 30%提高到 90%。CLEC2 和 CLEC5A/TLR2 在血小板-白细胞相互作用中的关键作用的确定将支持未来开发治疗急性病毒感染的新策略。
