Extracellular RNA facilitates hypoxia-induced leukocyte adhesion and infiltration in the lung through TLR3-IFN-γ-STAT1 signaling pathway
Extracellular RNA facilitates hypoxia-induced leukocyte adhesion and infiltration in the lung through TLR3-IFN-γ-STAT1 signaling pathway
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DOI：
10.1002/eji.201545597
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发表时间：
2015-11-01
影响因子：
5.4
通讯作者：
Khan, Gausal A.
中科院分区：
文献类型：
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作者：
Biswas, Indranil;Singh, Bandana;Khan, Gausal A.
从垂死细胞释放的内源性配体，包括细胞外RNA（eRNA），引起TLR活化，其与炎症和血管疾病相关。然而，这种反应在急性缺氧（AH）中的重要性仍未得到研究。在此，我们观察到在没有外源性病毒刺激的情况下，小鼠暴露于AH期间eRNA介导的TLR 3激活。RNaseA治疗减少了AH诱导的IFN和细胞粘附分子（CAM）的表达和肺中的髓样细胞浸润，TLR 3基因沉默或用抗体中和显著减弱了AH或聚I：C诱导的IFN和CAM表达和肺中的白细胞粘附（LA）和髓样细胞浸润。然而，RNaseA处理或TLR 3基因沉默未能改变AH诱导的肺血管细胞死亡和增殖。此外，IFN-γ-而不是IFN-α-调节AH诱导的CAM表达和LA。RNA酶A，TLR 3 siRNA，中和抗体，或STAT 1抑制剂治疗显着降低AH和聚I：C诱导的STAT 1磷酸化，CAM表达，和骨髓细胞浸润，表明在AH诱导的LA和浸润的STAT 1磷酸化的核心作用。我们的结论是，eRNA激活TLR 3和促进，通过在体内IFN-γ-STAT 1信号，AH诱导的白细胞浸润在肺。因此，RNaseA可能为肺部疾病患者提供一种治疗选择。
Endogenous ligands released from dying cells, including extracellular RNA (eRNA), cause TLR activation, which is associated with inflammation and vascular diseases. However, the importance of this response in acute hypoxia (AH) remains unexplored. Here, we observed eRNA-mediated TLR3 activation during exposure of mice to AH in the absence of exogenous viral stimuli. RNaseA treatment diminished AH-induced expression of IFN and cell adhesion molecules (CAMs) and myeloid cell infiltration in the lung, and TLR3 gene silencing or neutralization with antibodies markedly attenuated AH- or poly I: C-induced IFN and CAM expression and leukocyte adhesion (LA) and myeloid cell infiltration in the lung. However, RNaseA treatment or TLR3 gene silencing failed to alter AH-induced cell death and proliferation in lung vasculature. Furthermore, IFN-gamma-but not IFN-alpha-regulated AH-induced CAM expression and LA. Treatment with RNaseA, TLR3 siRNA, neutralizing antibodies, or a STAT1 inhibitor substantially decreased AH- and poly I: C-induced STAT1 phosphorylation, CAM expression, and myeloid cell infiltration, suggesting a central role for STAT1 phosphorylation in AH-induced LA and infiltration. We conclude that eRNA activates TLR3 and facilitates, through in vivo IFN-gamma-STAT1 signaling, AH-induced leukocyte infiltration in the lung. Thus, RNaseA might provide a therapeutic alternative for patients with lung diseases.