Platelets express functional Toll-like receptor-4
Platelets express functional Toll-like receptor-4
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DOI：
10.1182/blood-2005-03-0916
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发表时间：
2005-10-01
期刊：
影响因子：
20.3
通讯作者：
Kubes, P
中科院分区：
文献类型：
--
作者：
Andonegui, G;Kerfoot, SM;Kubes, P
严重的血小板减少症发生在人类败血症和注射脂多糖(LPS)的小鼠身上。越来越多的证据表明，血小板可能导致了这些异常，但这是内毒素激活血小板的直接结果还是其他炎症机制的间接结果尚不清楚。在这里，我们证明，尽管血小板不会增加P-选择素的表达来响应内毒素，但在流动条件下，血小板以Toll样受体-4(TLR4)依赖的方式与纤维蛋白原结合得更紧密。此外，我们发现从胎儿肝脏和成人循环血小板中培养的CD41(+)巨核细胞表达大量的TLR4。脂多糖可引起野生型小鼠的血小板减少，但对TLR4缺陷型(TLR4(Def))小鼠无此作用。野生型小鼠肺内聚集了野生型血小板，而TLR4(Def)血小板则没有。然而，脂多糖处理的TLR4(Def)小鼠的肺中并没有聚集野生型血小板。中性粒细胞也在肺部聚集，这先于血小板聚集。中性粒细胞耗尽可完全消除脂多糖诱导的血小板进入肺内，但血小板耗尽并不影响中性粒细胞聚集。因此，我们的数据首次表明，血小板确实表达TLR4的功能水平，TLR4通过中性粒细胞依赖的肺隔离对内毒素的反应导致血小板减少。
Profound thrombocytopenia occurs in humans with sepsis and in mice administered lipopolysaccharide (LPS). Growing evidence indicates that platelets may contribute to these abnormalities, but whether that is a direct result of LPS activation of platelets or an indirect result of other inflammatory mechanisms remains unclear. Here we demonstrate that although platelets do not increase P-selectin expression in response to LPS, platelets bind more avidly to fibrinogen under flow conditions in a Toll-like receptor-4 (TLR4)-dependent manner. In addition, we find that CD41(+) megakaryocytes grown from fetal livers and adult circulating platelets express significant amounts of TLR4. LPS induced thrombocytopenia in wild-type mice but not in TLR4-deficlent (TLR4(def)) mice. Wild-type platelets accumulated in the lungs of wild-type mice in response to LPS; TLR4(def) platelets did not. However, wild-type platelets did not accumulate in the lungs of LPS-treated TLR4(def) mice. Neutrophils also accumulated in the lungs, and this preceded platelet accumulation. Neutrophil depletion completely abolished LPS-induced platelet sequestration into the lungs, but platelet depletion did not affect neutrophil accumulation. Thus, our data show for the first time that platelets do express functional levels of TLR4, which contribute to thrombocytopenia through neutrophil-dependent pulmonary sequestration in response to LPS.