PPE57 induces activation of macrophages and drives Th1-type immune responses through TLR2
PPE57 induces activation of macrophages and drives Th1-type immune responses through TLR2
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DOI：
10.1007/s00109-014-1243-1
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发表时间：
2015-01
期刊：
影响因子：
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通讯作者：
Ying Xu;E. Yang;Qi Huang;Wenwen Ni;Cong Kong;Guoyuan Liu;Guanghua Li;Haibo Su;Honghai Wang
中科院分区：
文献类型：
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作者：
Ying Xu;E. Yang;Qi Huang;Wenwen Ni;Cong Kong;Guoyuan Liu;Guanghua Li;Haibo Su;Honghai Wang
脯氨酸-谷氨酸（PE）和脯氨酸-脯氨酸-谷氨酸（PPE）是分枝杆菌特有的相关蛋白，在调节先天免疫关键通路中起着不同的作用。在这项研究中，我们观察到PPE 57蛋白与细胞壁相关，并暴露在细胞表面。PPE 57增强分枝杆菌属（Mycobacteriumspp.）进入巨噬细胞并在巨噬细胞吞噬作用中起作用。为了探索潜在的机制，我们证明了PPE 57能够识别Toll样受体2（TLR 2），并通过增加巨噬细胞内几种细胞表面分子（CD 40，CD 80，CD 86和MHC II类）和促炎细胞因子（TNF-α，IL-6和IL-12 p40）的表达来进一步诱导巨噬细胞活化。这些分子参与丝裂原活化蛋白激酶（MAPK）和核因子κB（NF-κB）信号通路。我们证明PPE 57有效地极化T细胞以分泌干扰素（IFN）-γ和IL-2，并在体内和体外上调CXCR 3表达，这表明该蛋白可能有助于免疫反应期间的Th 1极化。此外，过表达PPE 57的重组卡介苗（BCG）对结核分枝杆菌的保护效果优于BCG。总之，我们的数据提供了几个证据，PPE 57可以通过与TLR 2相互作用来调节先天性和适应性免疫。这些结果表明，PPE 57蛋白是一个潜在的抗原，为合理设计的有效疫苗抗M。关键信息PPE 57位于细胞表面，可促进分枝杆菌进入巨噬细胞; PPE 57可直接与巨噬细胞表面的TLR 2相互作用; PPE 57以TLR 2依赖的方式在巨噬细胞活化中起关键作用; PPE 57通过TLR 2介导的巨噬细胞功能诱导Th 1免疫应答;过表达PPE 57的重组BCG可提高抗结核杆菌的保护效果。结核
AbstractProline-glutamic acid (PE) and proline-proline-glutamic acid (PPE) are related proteins exclusive toMycobacteriathat play diverse roles in modulating critical innate immune pathways. In this study, we observed that the PPE57 protein is associated with the cell wall and is exposed on the cell surface. PPE57 enhancesMycobacteriumspp. entering into macrophages and plays a role in macrophage phagocytosis. To explore the underlying mechanism, we demonstrated that PPE57 is able to recognise Toll-like receptor 2 (TLR2) and further induce macrophage activation by augmenting the expression of several cell surface molecules (CD40, CD80, CD86 and MHC class II) and pro-inflammatory cytokines (TNF-α, IL-6 and IL-12p40) within macrophages. These molecules are involved in the mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) signalling pathways. We demonstrated that PPE57 effectively polarises T cells to secrete interferon (IFN)-γ and IL-2 and to up-regulate CXCR3 expression in vivo and in vitro, suggesting that this protein may contribute to Th1 polarisation during the immune response. Moreover, recombinant Bacillus Calmette-Guérin (BCG) over-expressing PPE57 could provide better protective efficacy againstMycobacterium tuberculosischallenge compared with BCG. Taken together, our data provides several pieces of evidence that PPE57 may regulate innate and adaptive immunity by interacting with TLR2. These findings indicate that PPE57 protein is a potential antigen for the rational design of an efficient vaccine againstM. tuberculosis.Key messagesPPE57 is located on the cell surface and enhances mycobacterium entry into macrophage.PPE57 interacts directly with TLR2 on macrophages.PPE57 plays a key role in the activation of macrophages in a TLR2-dependent manner.PPE57 induces a Th1 immune response via TLR2-mediated macrophage functions.Recombinant BCG over-expressing PPE57 could improve protective efficacy againstM. tuberculosis.