RNA interference reveals a role for TLR2 and TLR3 in the recognition of Leishmania donovani promastigotes by interferon-γ-primed macrophages
RNA interference reveals a role for TLR2 and TLR3 in the recognition of Leishmania donovani promastigotes by interferon-γ-primed macrophages
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DOI：
10.1002/eji.200535079
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发表时间：
2006-02-01
影响因子：
5.4
通讯作者：
Descoteaux, A
中科院分区：
文献类型：
--
作者：
Flandin, JF;Chano, F;Descoteaux, A
杜氏利什曼原虫前鞭毛体在入侵幼稚巨噬细胞期间逃避促炎反应的诱导。然而，它们进入IFN-γ引发的巨噬细胞伴随着一氧化氮（NO）和促炎细胞因子的分泌。在本研究中，我们提出了这样的假设，即IFN-γ诱导小鼠巨噬细胞识别L。donovani promastigotes.我们观察到，在IFN-γ致敏的巨噬细胞中，L。donovani前鞭毛体刺激白细胞介素-1受体相关激酶-1（IRAK-1）活性。我们接下来表明，Toll样受体（TLR）3在幼稚巨噬细胞中几乎检测不到，但在IFN-γ处理的巨噬细胞中表达。通过RNA干扰技术沉默TLR 3、TLR 2、IRAK-1和MyD 88的表达，揭示了TLR和IRAK-1均参与了L. donovani promastigotes.利用L. donovani突变体，我们表明TLR 2介导的反应依赖于Gal β 1，4 Man α-PO 4-含有磷酸聚糖，而TLR 3介导的反应是独立的这些糖缀合物。此外，我们的数据表明TLR 2和TLR 3参与了L. donovani前鞭毛体和TLR 3在IFN-γ引发的巨噬细胞的杀利什曼活性中的作用。总的来说，我们的数据与L. Donovani前鞭毛体的表达依赖于巨噬细胞活化状态并需要TLR 3的表达。
Leishmania donovani promastigotes evade the induction of a proinflammatory response during their invasion of naive macrophages. However,,their entry into IFN-gamma-primed macrophages is accompanied by the secretion of nitric oxide (NO) and proinflammatory cytokines. In the present study, we addressed the hypothesis that priming with IFN-gamma induces the expression of a receptor that enables mouse macrophages to recognize L. donovani promastigotes. We observed that in IFN-gamma-primed macrophages, L. donovani promastigotes stimulated Interleukin-1 receptor-associated kinase-1 (IRAK-1) activity. We next showed that Toll-like receptor (TLR) 3 is barely detectable in naive macrophages but is expressed in IFN-gamma-treated macrophages. Silencing of TLR3, TLR2, IRAK-1 and myeloid differentiation factor 88 (MyD88) expression by RNA interference revealed that both TLR are involved in the secretion of NO and TNF-alpha induced by L. donovani promastigotes. Using L. donovani mutants, we showed that TLR2-mediated responses are dependent on Gal beta 1,4Man alpha-PO4-containing phosphoglycans, whereas TLR3-mediated responses are independent of these glycoconjugates. Furthermore, our data indicate a participation of TLR2 and TLR3 in the phagocytosis of L. donovani promastigotes and a role for TLR3 in the leishmanicidal activity of the IFN-gamma-primed macrophages. Collectively, our data are consistent with a model where recognition of L. donovani promastigotes depends on the macrophage activation status and requires the expression of TLR3.