Mannodendrimers prevent acute lung inflammation by inhibiting neutrophil recruitment
Mannodendrimers prevent acute lung inflammation by inhibiting neutrophil recruitment
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DOI：
10.1073/pnas.1221708110
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发表时间：
2013-05-28
影响因子：
11.1
通讯作者：
Puzo, Germain
中科院分区：
文献类型：
--
作者：
Blattes, Emilyne;Vercellone, Alain;Puzo, Germain
结核分枝杆菌甘露糖封端的脂阿拉伯甘露聚糖通过靶向C型凝集素受体DC特异性细胞间粘附分子3-抓取非整合素（DC-SIGN）抑制LPS刺激的人树突状细胞（DC）释放促炎细胞因子。为了模拟甘露糖封端的脂阿拉伯甘露聚糖的生物活性超分子结构，我们设计并合成了一组接枝有甘露糖单元的聚（磷酰腙）树枝状聚合物，称为甘露树枝状聚合物，其大小、数量和长度不同，其（α 1 -> 2）-寡甘露糖苷帽。具有48个三甘露糖苷帽的第三代树枝状聚合物（3 T）和具有96个二甘露糖苷的第四代树枝状聚合物（4D）显示出对DC-SIGN的最高结合亲合力。此外，这些树枝状聚合物以DC-SIGN依赖性方式抑制LPS刺激的DC产生促炎细胞因子，包括TNF-α。最后，在小鼠暴露于雾化LPS的急性肺部炎症模型中，发现经口施用3 T甘露树枝状聚合物通过靶向DC-SIGN鼠同源物SIGN相关1显著减少嗜中性粒细胞流入。因此，3 T mannodendrimer代表了一种用于治疗肺炎性疾病的创新的全合成化合物。
Mycobacterium tuberculosis mannose-capped lipoarabinomannan inhibits the release of proinflammatory cytokines by LPS-stimulated human dendritic cells (DCs) via targeting the C-type lectin receptor DC-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN). With the aim of mimicking the bioactive supramolecular structure of mannose-capped lipoarabinomannan, we designed and synthesized a set of poly(phosphorhydrazone) dendrimers grafted with mannose units, called mannodendrimers, that differed by size and the number and length of their (alpha 1 -> 2)-oligommanoside caps. A third-generation dendrimer bearing 48 trimannoside caps (3T) and a fourth-generation dendrimer bearing 96 dimannosides (4D) displayed the highest binding avidity for DC-SIGN. Moreover, these dendrimers inhibited proinflammatory cytokines, including TNF-alpha, production by LPS-stimulated DCs in a DC-SIGN-dependent fashion. Finally, in a model of acute lung inflammation in which mice were exposed to aerosolized LPS, per os administration of 3T mannodendrimer was found to significantly reduce neutrophil influx via targeting the DC-SIGN murine homolog SIGN-related 1. The 3T mannodendrimer therefore represents an innovative fully synthetic compound for the treatment of lung inflammatory diseases.