Orphan nuclear receptor TR3/Nur77 improves wound healing by upregulating the expression of integrin β4
Orphan nuclear receptor TR3/Nur77 improves wound healing by upregulating the expression of integrin β4
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孤儿核受体 TR3/Nur77 通过上调整合素 β 4 的表达来改善伤口愈合
DOI：
10.1096/fj.14-257550
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发表时间：
2015-01-01
期刊：
影响因子：
4.8
通讯作者：
Zeng, Huiyan
中科院分区：
文献类型：
--
作者：
Niu, Gengming;Ye, Taiyang;Zeng, Huiyan
组织修复/伤口愈合是许多疾病的关键步骤，包括慢性伤口、心肌梗死、中风、癌症和炎症，其中血管生成起重要作用。最近，我们首次报道了孤儿核受体TR 3/Nur 77是血管生成及其相关微血管通透性的关键介质。在Nur 77基因敲除小鼠中，VEGF-A、组胺和血清素诱导的肿瘤生长和血管生成几乎完全受到抑制。然而，尚不清楚TR 3/Nur 77是否在伤口愈合中发挥任何作用。在这些研究中，在具有各种Nur 77活性的3种类型的遗传修饰小鼠中进行皮肤伤口愈合测定。我们发现小鼠内皮细胞中Nur 77的异位诱导足以改善皮肤伤口愈合。尽管Nur 77基因敲除小鼠的皮肤伤口愈合与野生型对照小鼠相当，但该过程在EC-Nur 77-DN小鼠中显著延迟，其中显性负性Nur 77突变体在小鼠内皮细胞中诱导并特异性表达。通过功能丧失试验，我们阐明了一种新的前馈信号通路，整合素β 4。PI 3 K-> Akt -> FAK，TR 3通过其介导HUVEC迁移。此外，TR 3/Nur 77通过靶向其启动子活性调节整联蛋白β 4的表达。总之，TR 3/Nur 77的表达通过靶向整合素β 4来改善伤口愈合。TR 3/Nur 77是促血管生成治疗的潜在候选药物。结果进一步表明，TR 3/Nur 77是病理性血管生成所需的，但不是发育/生理性血管生成所需的，并且Nur 77及其家族成员在正常皮肤伤口愈合中起着多余的作用。
Tissue repair/wound healing, in which angiogenesis plays an important role, is a critical step in many diseases including chronic wound, myocardial infarction, stroke, cancer, and inflammation. Recently, we were the first to report that orphan nuclear receptor TR3/Nur77 is a critical mediator of angiogenesis and its associated microvessel permeability. Tumor growth and angiogenesis induced by VEGF-A, histamine, and serotonin are almost completely inhibited in Nur77 knockout mice. However, it is not known whether TR3/Nur77 plays any roles in wound healing. In these studies, skin wound-healing assay was performed in 3 types of genetically modified mice having various Nur77 activities. We found that ectopic induction of Nur77 in endothelial cells of mice is sufficient to improve skin wound healing. Although skin wound healing in Nur77 knockout mice is comparable to the wild-type control mice, the process is significantly delayed in the EC-Nur77-DN mice, in which a dominant negative Nur77 mutant is inducibly and specifically expressed in mouse endothelial cells. By a loss-of-function assay, we elucidate a novel feed-forward signaling pathway, integrin beta 4. PI3K -> Akt -> FAK, by which TR3 mediates HUVEC migration. Furthermore, TR3/Nur77 regulates the expression of integrin beta 4 by targeting its promoter activity. In conclusion, expression of TR3/Nur77 improves wound healing by targeting integrin beta 4. TR3/Nur77 is a potential candidate for proangiogenic therapy. The results further suggest that TR3/Nur77 is required for pathologic angiogenesis but not for developmental/physiologic angiogenesis and that Nur77 and its family members play a redundant role in normal skin wound healing.