Lipopolysaccharide Promotes Choroidal Neovascularization by Up-Regulation of CXCR4 and CXCR7 Expression in Choroid Endothelial Cell.
Lipopolysaccharide Promotes Choroidal Neovascularization by Up-Regulation of CXCR4 and CXCR7 Expression in Choroid Endothelial Cell.
复制标题
脂多糖通过上调脉络膜内皮细胞CXCR4和CXCR7表达促进脉络膜新生血管形成。
DOI：
10.1371/journal.pone.0136175
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Shen MQ
中科院分区：
文献类型：
--
作者：
Feng YF;Guo H;Yuan F;Shen MQ
基质细胞衍生因子-1（SDF-1）已被证实通过其两种受体：CXC趋化因子受体4（CXCR 4）和CXCR 7参与脉络膜新生血管（CNV）的形成。以往的研究表明，脂多糖（LPS）激活Toll样受体（TLR）可能会提高CXCR 4和/或CXCR 7在肿瘤细胞中的表达，增强对SDF-1的反应，以促进侵袭和细胞播散。然而，LPS对内皮细胞中CXCR 4和CXCR 7表达以及随后的病理性血管生成的影响仍有待阐明。目前的研究表明，LPS通过激活脉络膜视网膜内皮细胞（RF/6A）中的TLR 4途径增强CXCR 4和CXCR 7的表达。此外，LPS对CXCR 4和CXCR 7的转录调控是通过细胞外信号相关激酶（ERK）1/2的磷酸化和核因子κ B（NF-κB）信号通路的激活介导的，这些信号通路可被ERK或NF-κ B特异性抑制剂阻断。此外，增加CXCR 4和CXCR 7表达导致增加SDF-1诱导的RF/6A细胞增殖、迁移和管形成。在体内，LPS治疗组大鼠的CXCR 4和CXCR 7的mRNA表达水平显著高于对照组，激光诱导的CNV面积也显著大于对照组。在单次玻璃体内注射LPS处理的大鼠中，用中和抗体阻断SDF-1可减弱CNV的进展。总而言之，这些结果表明LPS可能通过增强内皮细胞中CXCR 7和CXCR 7的表达来影响CNV的形成，这可能为CNV相关疾病的治疗提供了新的视角。
Stromal cell-derived factor-1 (SDF-1) has been confirmed to participate in the formation of choroidal neovascularization (CNV) via its two receptors: CXC chemokine receptors 4 (CXCR4) and CXCR7. Previous studies have indicated that the activation of Toll-like receptors (TLRs) by lipopolysaccharide (LPS) might elevate CXCR4 and/or CXCR7 expression in tumor cells, enhancing the response to SDF-1 to promote invasion and cell dissemination. However, the impact of LPS on the CXCR4 and CXCR7 expression in endothelial cells and subsequent pathological angiogenesis formation remains to be elucidated. The present study shows that LPS enhanced the CXCR4 and CXCR7 expression via activation of the TLR4 pathway in choroid-retinal endothelial (RF/6A) cells. In addition, the transcriptional regulation of CXCR4 and CXCR7 by LPS was found to be mediated by phosphorylation of the extracellular signal-related kinase (ERK) 1/2 and activation of nuclear factor kappa B (NF-κB) signaling pathways, which were blocked by ERK- or NF-κB-specific inhibitors. Furthermore, the increased CXCR4 and CXCR7 expression resulted in increased SDF-1-induced RF/6A cells proliferation, migration and tube formation. In vivo, LPS-treated rat had significantly higher mRNA levels of CXCR4 and CXCR7 expression and lager laser-induced CNV area than vehicle-treated rat. SDF-1 blockade with a neutralizing antibody attenuated the progression of CNV in LPS-treated rat after a single intravitreal injection. Altogether, these results demonstrated that LPS might influence CNV formation by enhancing CXCR7 and CXCR7 expression in endothelial cells, possibly providing a new perspective for the treatment of CNV-associated diseases.