Human integrin α(3)β(1) regulates TLR2 recognition of lipopeptides from endosomal compartments.
Human integrin α(3)β(1) regulates TLR2 recognition of lipopeptides from endosomal compartments.
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DOI：
10.1371/journal.pone.0012871
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发表时间：
2010-09-22
期刊：
影响因子：
3.7
通讯作者：
Hu LT
中科院分区：
文献类型：
--
作者：
Marre ML;Petnicki-Ocwieja T;DeFrancesco AS;Darcy CT;Hu LT
Toll样受体（TLR）-2/TLR1异二聚体识别细菌脂肽并启动炎症介质的产生。介导这一过程的适配器和辅助受体，以及这些适配器和辅助受体发挥作用的机制仍在探索中。使用shRNA、阻断抗体和荧光显微镜，我们发现U937巨噬细胞对TLR 2/1配体Pam 3CSK 4的反应依赖于整合素α3β1。整合素α3β1参与TLR 2/1信号传导的机制是通过其在脂肽的内吞作用中的作用。使用内体酸化/成熟的抑制剂和配体的物理束缚，我们表明Pam 3CSK 4的内吞作用对于完整的TLR 2/1介导的促炎细胞因子应答是必要的。我们还表明，TLR 2/1信号从内涵体的结果在不同的炎症介质的诱导比TLR 2/1信号从质膜。在这里，我们确定整合素α3β1作为一种新的细菌脂肽识别调节剂。我们证明了特定细胞因子亚群的诱导依赖于整合素α3β1介导的配体内吞作用。此外，我们解决了一个正在进行的争论，关于细菌脂肽的内体识别表明，TLR 2/1信号从内体车厢以及质膜，下游反应可能会有所不同，这取决于受体定位。我们认为整合素α3β1对内体TLR 2/1信号的调节是调节炎症反应的一种机制。
Toll-like receptor (TLR)-2/TLR1 heterodimers recognize bacterial lipopeptides and initiate the production of inflammatory mediators. Adaptors and co-receptors that mediate this process, as well as the mechanisms by which these adaptors and co-receptors function, are still being discovered. Using shRNA, blocking antibodies, and fluorescent microscopy, we show that U937 macrophage responses to the TLR2/1 ligand, Pam3CSK4, are dependent upon an integrin, α3β1. The mechanism for integrin α3β1 involvement in TLR2/1 signaling is through its role in endocytosis of lipopeptides. Using inhibitors of endosomal acidification/maturation and physical tethering of the ligand, we show that the endocytosis of Pam3CSK4 is necessary for the complete TLR2/1-mediated pro-inflammatory cytokine response. We also show that TLR2/1 signaling from the endosome results in the induction of different inflammatory mediators than TLR2/1 signaling from the plasma membrane. Here we identify integrin α3β1 as a novel regulator for the recognition of bacterial lipopeptides. We demonstrate that induction of a specific subset of cytokines is dependent upon integrin α3β1-mediated endocytosis of the ligand. In addition, we address an ongoing controversy regarding endosomal recognition of bacterial lipopeptides by demonstrating that TLR2/1 signals from within endosomal compartments as well as the plasma membrane, and that downstream responses may differ depending upon receptor localization. We propose that the regulation of endosomal TLR2/1 signaling by integrin α3β1 serves as a mechanism for modulating inflammatory responses.
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影响因子：
3.1
作者：
Behera, AK;Hildebrand, E;Hu, LT
通讯作者：
Hu, LT
I型Interferon自分泌 - 核酸环与树突状细胞的Toll样受体诱导的白介素-12p70分泌有关。
影响因子：
15.3
作者：
Gautier, G;Humbert, M;Deauvieau, F;Scuiller, M;Hiscott, J;Bates, EEM;Trinchieri, G;Caux, C;Garrone, P
通讯作者：
Garrone, P
影响因子：
4.4
作者：
Behera, Aruna K.;Hildebrand, Ethan;Hu, Linden T.
通讯作者：
Hu, Linden T.
影响因子：
64.8
作者：
Horng, T;Barton, GM;Medzhitov, R
通讯作者：
Medzhitov, R
DOI：
10.1073/pnas.90.15.7059
发表时间：
1993-08-01
影响因子：
11.1
作者：
COBURN, J;LEONG, JM;ERBAN, JK
通讯作者：
ERBAN, JK