Activation of human monocytes by live Borrelia burgdorferi generates TLR2-dependent and -independent responses which include induction of IFN-beta.
Activation of human monocytes by live Borrelia burgdorferi generates TLR2-dependent and -independent responses which include induction of IFN-beta.
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DOI：
10.1371/journal.ppat.1000444
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发表时间：
2009-05
期刊：
影响因子：
6.7
通讯作者：
Radolf JD
中科院分区：
文献类型：
--
作者：
Salazar JC;Duhnam-Ems S;La Vake C;Cruz AR;Moore MW;Caimano MJ;Velez-Climent L;Shupe J;Krueger W;Radolf JD
人们普遍认为，对伯氏疏螺旋体（Borrelia burgdorferi，Bb）的先天性免疫应答主要由螺旋体的外膜脂蛋白通过细胞表面TLR 1/2信号传导而触发。最近，我们挑战了这一概念，证明了外周血单核细胞（PBMC）的吞噬活Bb引起更大的生产促炎细胞因子比等效的细菌裂解物。使用全基因组微阵列，我们在本文中显示，与裂解物相比，活螺旋体引起更强烈和更广泛的转录反应，涉及与不同细胞过程相关的基因;其中包括IFN-β和许多干扰素刺激的基因（ISG），这些基因未知是否由TLR 2信号传导引起。使用分离的单核细胞，我们证明了由活Bb引起的细胞活化信号来自细胞表面相互作用以及吞噬体内生物体的摄取和降解。与PBCM一样，活Bb在单核细胞中诱导的TNF-α、IL-6、IL-10和IL-1β的转录和分泌显著高于裂解物。与IL-1β一样，分泌的IL-18也需要被活化的半胱天冬酶-1切割，仅在对活Bb的应答中产生。促炎性细胞因子的产生TLR 2缺陷的小鼠巨噬细胞只适度减少，在响应活Bb，但对裂解物的大幅受损; TLR 2缺陷的螺旋体的摄取和降解没有显着的影响。与PBMC一样，在分离的单核细胞中，活的Bb是比裂解物或合成的TLR 2激动剂更有效的IFN-β和ISG诱导剂。总的来说，我们的研究结果表明，增强的先天性免疫反应的单核细胞吞噬活Bb具有TLR 2依赖性和非依赖性的组件，后者诱导I型IFN和ISGs的转录。莱姆病是由螺旋体病原体伯氏疏螺旋体（Borrelia burgdorferi，Bb）引起的蜱传播的传染性疾病。对Bb的天然免疫应答被认为是由螺旋体的外膜脂蛋白通过细胞表面toll样受体（TLR 1/2）信号传导触发的。使用全基因组微阵列技术，我们发现，活螺旋体引起更强烈和更广泛的免疫反应，在人外周血单核细胞（PBMC）比可以简单地解释由TLR 1/2细胞表面刺激。特别令人感兴趣的是，活Bb也独特地诱导I型干扰素的转录。在类似刺激的分离人单核细胞中，活Bb产生更多促炎和抗炎细胞因子（TNF-α、IL-6、IL-10和IL-1β）以及干扰素-β（IFN-β）。分泌的IL-18与IL-1β一样，需要通过活化的半胱天冬酶-1对其无活性形式进行胞质裂解，仅在响应活Bb时产生。尽管有证据表明被吞噬的螺旋体在吞噬体空泡中迅速降解，并且无法毫发无损地逃逸到细胞胞质溶胶中，但胞质溶胶反应仍发生。我们的结论是，先天免疫信号产生的人单核细胞吞噬螺旋体允许主机控制细菌通过一些非排他性的途径，这是TLR 2依赖性和非依赖性，包括I型干扰素反应。
It is widely believed that innate immune responses to Borrelia burgdorferi (Bb) are primarily triggered by the spirochete's outer membrane lipoproteins signaling through cell surface TLR1/2. We recently challenged this notion by demonstrating that phagocytosis of live Bb by peripheral blood mononuclear cells (PBMCs) elicited greater production of proinflammatory cytokines than did equivalent bacterial lysates. Using whole genome microarrays, we show herein that, compared to lysates, live spirochetes elicited a more intense and much broader transcriptional response involving genes associated with diverse cellular processes; among these were IFN-β and a number of interferon-stimulated genes (ISGs), which are not known to result from TLR2 signaling. Using isolated monocytes, we demonstrated that cell activation signals elicited by live Bb result from cell surface interactions and uptake and degradation of organisms within phagosomes. As with PBCMs, live Bb induced markedly greater transcription and secretion of TNF-α, IL-6, IL-10 and IL-1β in monocytes than did lysates. Secreted IL-18, which, like IL-1β, also requires cleavage by activated caspase-1, was generated only in response to live Bb. Pro-inflammatory cytokine production by TLR2-deficient murine macrophages was only moderately diminished in response to live Bb but was drastically impaired against lysates; TLR2 deficiency had no significant effect on uptake and degradation of spirochetes. As with PBMCs, live Bb was a much more potent inducer of IFN-β and ISGs in isolated monocytes than were lysates or a synthetic TLR2 agonist. Collectively, our results indicate that the enhanced innate immune responses of monocytes following phagocytosis of live Bb have both TLR2-dependent and -independent components and that the latter induce transcription of type I IFNs and ISGs. Lyme disease is a tick-borne infectious disorder caused by the spirochetal pathogen Borrelia burgdorferi (Bb). Innate immune responses to Bb are thought to be triggered by the spirochete's outer membrane lipoproteins signaling through cell surface toll-like receptors (TLR1/2). Using a whole genome microarray technique, we showed that live spirochetes elicited a more intense and broader immune response in human peripheral blood mononuclear cells (PBMCs) than could be explained simply by TLR1/2 cell surface stimulation. Of particular interest, live Bb also uniquely induced transcription of type I interferons. In similarly stimulated isolated human monocytes, live Bb generated a greater production of pro- and anti-inflammatory cytokines (TNF-α, IL-6, IL-10 and IL-1β), as well as interferon-β (IFN-β). Secreted IL-18, which like IL-1β requires cytosolic cleavage of its inactive form by activated caspase-1, was generated only in response to live Bb. The cytosolic responses occurred despite evidence that phagocytosed spirochetes were rapidly degraded in phagosomal vacuoles, and unable to escape unscathed into the cell cytosol. We conclude that the innate immune signals generated in human monocytes by phagocytosed spirochetes allow the host to control the bacterium through a number of non-exclusive pathways, that are both TLR2-dependent and -independent, and include a type I interferon response.
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