Endothelial reticulon-4B (Nogo-B) regulates ICAM-1-mediated leukocyte transmigration and acute inflammation
Endothelial reticulon-4B (Nogo-B) regulates ICAM-1-mediated leukocyte transmigration and acute inflammation
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DOI：
10.1182/blood-2010-04-281956
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发表时间：
2011-02-17
期刊：
影响因子：
20.3
通讯作者：
Sessa, William C.
中科院分区：
文献类型：
--
作者：
Di Lorenzo, Annarita;Manes, Thomas D.;Sessa, William C.
网状蛋白(RTN)家族主要定位于大多数细胞的内质网(ER)。RTN-4家族(又名Nogo)由名为RTN-4A、RTN-4B和RTN-4C的常见基因的3个剪接变体组成。最近，我们在血管壁内皮细胞和平滑肌细胞中发现了RTN-4B(Nogo-B)蛋白，表明Nogo-B在体外是细胞迁移和体内血管重塑和血管生成的调节因子。然而，Nogo-B在炎症中的作用在很大程度上仍不清楚。在本研究中，我们使用两种炎症模型来证明内皮Nogo-B调节白细胞迁移和细胞间黏附分子-1(ICAM-1)依赖的信号转导。缺乏Nogo-A/B的小鼠在炎症部位的中性粒细胞和单核细胞募集显著减少，而移植野生型(WT)骨髓的Nogo-A/B(-/-)小鼠与移植Nogo-A/B(-/-)骨髓的WT小鼠相比，仍然表现出受损的炎症反应，这表明宿主Nogo在这一反应中发挥了关键作用。利用人白细胞和内皮细胞，我们从机制上证明了用小干扰RNA(SiRNA)沉默Nogo-B会削弱中性粒细胞的迁移，并减少ICAM-1刺激的血管内皮细胞钙粘附素(VE-cadherin)的磷酸化。我们的结果揭示了内皮细胞Nogo-B在基本免疫功能中的新作用，并在调控内皮细胞调节滞育的分子网络中提供了关键环节。(血。2011；117(7)：2284-2295)
The reticulon (Rtn) family of proteins are localized primarily to the endoplasmic reticulum (ER) of most cells. The Rtn-4 family, (aka Nogo) consists of 3 splice variants of a common gene called Rtn-4A, Rtn-4B, and Rtn-4C. Recently, we identified the Rtn-4B (Nogo-B) protein in endothelial and smooth muscle cells of the vessel wall, and showed that Nogo-B is a regulator of cell migration in vitro and vascular remodeling and angiogenesis in vivo. However, the role of Nogo-B in inflammation is still largely unknown. In the present study, we use 2 models of inflammation to show that endothelial Nogo-B regulates leukocyte transmigration and intercellular adhesion molecule-1 (ICAM-1)-dependent signaling. Mice lacking Nogo-A/B have a marked reduction in neutrophil and monocyte recruitment to sites of inflammation, while Nogo-A/B(-/-) mice engrafted with wild-type (WT) bone marrow still exhibit impaired inflammation compared with WT mice engrafted with Nogo-A/B(-/-) bone marrow, arguing for a critical role of host Nogo in this response. Using human leukocytes and endothelial cells, we show mechanistically that the silencing of Nogo-B with small interfering RNA (siRNA) impairs the transmigration of neutrophils and reduces ICAM-1-stimulated phosphorylation of vascular endothelial-cell cadherin (VE-cadherin). Our results reveal a novel role of endothelial Nogo-B in basic immune functions and provide a key link in the molecular network governing endothelial-cell regulation of diapedesis. (Blood. 2011;117(7):2284-2295)