Division of Molecular Medicine, Bose Institute, Kolkata -700054, India.
J Infect Dis. 2010 Jul 1;202(1):145-55. doi: 10.1086/653210.
Visceral leishmaniasis is characterized by severe immunosuppression of the host cell, resulting in loss of the proinflammatory response. Toll-like receptor 2 (TLR2) is involved in myriad disease forms, including visceral leishmaniasis. During Leishmania donovani infection, the parasite modulates TLR2 to suppress interleukin 12 production, indicating the possible involvement of TLR2 in regulation of the immune response against L. donovani infection. Arabinosylated lipoarabinomannan (Ara-LAM) possesses immunomodulatory properties and induces proinflammatory responses via induction of TLR2-mediated signaling. Here, we found that pretreatment of L. donovani-infected macrophages with Ara-LAM caused a significant increase in TLR2 expression along with the activation of TLR2-mediated downstream signaling, facilitating active nuclear translocation of nuclear factor kappaB. These events culminated in up-regulation of the proinflammatory response, which was abrogated by treatment with TLR2-specific small interfering RNA. In vivo experiments were also suggestive of Ara-LAM playing a long-term protective role. This study demonstrates that Ara-LAM confers protection against leishmanial pathogenesis via TLR2 signaling-mediated induction of the proinflammatory response.
内脏利什曼病的特征是宿主细胞严重免疫抑制，导致促炎反应丧失。Toll 样受体 2（TLR2）参与多种疾病形式，包括内脏利什曼病。在感染杜氏利什曼原虫时，寄生虫调节 TLR2 以抑制白细胞介素 12 的产生，表明 TLR2 可能参与调节针对 L. donovani 感染的免疫反应。阿拉伯糖基化脂阿拉伯甘露聚糖（Ara-LAM）具有免疫调节特性，并通过诱导 TLR2 介导的信号转导诱导促炎反应。在这里，我们发现，用 Ara-LAM 预处理感染利什曼原虫的巨噬细胞会导致 TLR2 表达显著增加，同时激活 TLR2 介导的下游信号转导，促进核因子 kappaB 的主动核转位。这些事件最终导致促炎反应的上调，而用 TLR2 特异性小干扰 RNA 处理则会阻断这一过程。体内实验也表明 Ara-LAM 发挥长期保护作用。本研究表明，Ara-LAM 通过 TLR2 信号转导介导的促炎反应诱导，对利什曼病的发病机制提供保护。
