Inhibition of Orail-mediated Ca2+ entry limits endothelial cell inflammation by suppressing, calcineurin-NFATc4 signaling pathway
Inhibition of Orail-mediated Ca2+ entry limits endothelial cell inflammation by suppressing, calcineurin-NFATc4 signaling pathway
复制标题
抑制Orai1介导的Ca2进入通过抑制钙调神经磷酸酶-NFATc4信号通路来限制内皮细胞炎症
DOI：
10.1016/j.bbrc.2017.12.034
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发表时间：
2018-01-08
影响因子：
3.1
通讯作者：
Liang, Si-Jia
中科院分区：
文献类型：
--
作者：
Yu, Bei-Xin;Yuan, Jia-Ni;Liang, Si-Jia
Orail依赖性Ca 2+内流通过调节T细胞和巨噬细胞活化以及中性粒细胞浸润在炎症反应中起重要作用。然而，Orail Ca 2+进入是否有助于内皮激活，血管炎症的早期步骤之一，仍然难以捉摸。在本研究中，我们观察到Orail的敲低降低了TNF-α诱导的粘附分子如ICAM-1和VCAM-1在HUVEC中的表达，而Orail的过表达增强了TNF-α诱导的粘附分子如ICAM-1和VCAM-1在HUVEC中的表达，随后阻断了单核细胞与HUVEC 5的粘附。在体内，Orail下调减弱了TNF α诱导的小鼠主动脉中ICAM-1和VCAM-1的表达以及血清中促炎细胞因子的水平。此外，Orail敲低还显著降低了TNF α治疗后肺中促炎细胞因子的表达和中性粒细胞浸润，从而保护了肺组织损伤。值得注意的是，在活化T细胞核因子（NFAT 5）的所有同种型中，TNF α仅触发HUVEC中的NFATc 4核积累。Orail的敲除或钙调神经磷酸酶的抑制阻止TNF-α诱导的NFATc 4核转位，并减少ICAM-1和VCAM-1在HUVEC 5中的表达。过表达NFATc 4进一步增强TNF α诱导的ICAM-1和VCAM-1表达。我们的研究表明，Orai 1-Ca 2-calcineurin-NFATc 4信号转导是TNF α诱导的内皮细胞活化和血管炎症所需的重要炎症通路。因此，Orail可能成为治疗炎症性疾病的潜在靶点。(C)2017爱思唯尔公司All rights reserved.
Orail-dependent Ca2+ entry plays an essential role in inflammatory response through regulating T cell and macrophage activation and neutrophil infiltration. However, whether Orail Ca2+ entry contributes to endothelial activation, one of the early steps of vascular inflammation, remains elusive. In the present study, we observed that knockdown of Orail reduced, whereas overexpression of Orail potentiated, TNF-alpha-induced expression of adhesion molecules such as ICAM-1 and VCAM-1 in HUVECs, and subsequently blocked adhesion of monocyte to HUVEC5. In vivo, Orail downregulation attenuated TNFa.induced ICAM-1 and VCAM-1 expression in mouse aorta and the levels of pro-inflammatory cytokines in the serum. In addition, Orail knockdown also dramatically decreased the expression of pro inflammatory cytokines and neutrophil infiltration in the lung after TNFa treatment, and thus protected lung tissue injury. Notably, among all isoforms of nuclear factor of activated T cells (NFAT5), TNF alpha only triggered NFATc4 nuclear accumulation in HUVECs. Knockdown of Orail or inhibition of calcineurin prevented TNF-alpha-induced NFATc4 nuclear translocation and reduced ICAM-1 and VCAM-1 expression in HUVEC5. Overexpression of NFATc4 further enhanced ICAM-1 and VCAM-1 expression induced by TNF alpha. Our study demonstrates that Orai1-Ca2-calcineurin-NFATc4 signaling is an essential inflammatory pathway required for TNF alpha-induced endothelial cell activation and vascular inflammation. Therefore, Orail may be a potential therapeutic target for treatment of inflammatory diseases. (C) 2017 Elsevier Inc. All rights reserved.