A key role for the endothelium in NOD1 mediated vascular inflammation: comparison to TLR4 responses.
A key role for the endothelium in NOD1 mediated vascular inflammation: comparison to TLR4 responses.
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DOI：
10.1371/journal.pone.0042386
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Mitchell JA
中科院分区：
文献类型：
--
作者：
Gatheral T;Reed DM;Moreno L;Gough PJ;Votta BJ;Sehon CA;Rickard DJ;Bertin J;Lim E;Nicholson AG;Mitchell JA
了解病原体诱导血管炎症和功能障碍的机制可能会揭示脓毒症及相关病症的新治疗靶点。细胞内受体 NOD1 识别革兰氏阴性菌和一些革兰氏阳性菌细胞壁中的肽聚糖。 NOD1 参与通过激活 NFκB 和 MAPK 通路产生炎症反应。我们之前已经证明，刺激 NOD1 会直接激活血管并引起体内实验性休克。在这项研究中，我们使用离体血管器官培养模型来表征内皮细胞在血管对 NOD1 激动剂反应中的相对贡献。此外，我们还提出了 NOD1 直接激活人体血管的新发现。使用人类培养细胞，我们证实内皮细胞比血管平滑肌细胞对 NOD1 激动剂的反应更强烈。因此，我们试图从药理学上区分人内皮细胞中 NOD1 和 TLR4 介导的信号通路，重点关注 TAK1、NFκB 和 p38 MAPK。此外，我们还研究了 RIP2 和 NOD1 本身的新型抑制剂，它们特异性抑制 NOD1 配体诱导的脉管系统炎症信号传导。本文首次证明了 NOD1 刺激可激活整个人体动脉，以及内皮细胞在血管感知 NOD1 配体中的相对重要性。该数据支持 NOD1 和 RIP2 作为以血管炎症为临床特征的人类疾病（例如脓毒症和感染性休克）的治疗靶点的潜在用途。
Understanding the mechanisms by which pathogens induce vascular inflammation and dysfunction may reveal novel therapeutic targets in sepsis and related conditions. The intracellular receptor NOD1 recognises peptidoglycan which features in the cell wall of Gram negative and some Gram positive bacteria. NOD1 engagement generates an inflammatory response via activation of NFκB and MAPK pathways. We have previously shown that stimulation of NOD1 directly activates blood vessels and causes experimental shock in vivo. In this study we have used an ex vivo vessel-organ culture model to characterise the relative contribution of the endothelium in the response of blood vessels to NOD1 agonists. In addition we present the novel finding that NOD1 directly activates human blood vessels. Using human cultured cells we confirm that endothelial cells respond more avidly to NOD1 agonists than vascular smooth muscle cells. Accordingly we have sought to pharmacologically differentiate NOD1 and TLR4 mediated signalling pathways in human endothelial cells, focussing on TAK1, NFκB and p38 MAPK. In addition we profile novel inhibitors of RIP2 and NOD1 itself, which specifically inhibit NOD1 ligand induced inflammatory signalling in the vasculature. This paper is the first to demonstrate activation of whole human artery by NOD1 stimulation and the relative importance of the endothelium in the sensing of NOD1 ligands by vessels. This data supports the potential utility of NOD1 and RIP2 as therapeutic targets in human disease where vascular inflammation is a clinical feature, such as in sepsis and septic shock.
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