Intraocular expression and release of high-mobility group box 1 protein in retinal detachment
Intraocular expression and release of high-mobility group box 1 protein in retinal detachment
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DOI：
10.1038/labinvest.2008.165
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发表时间：
2009-03-01
影响因子：
5
通讯作者：
Maruyama, Ikuro
中科院分区：
文献类型：
--
作者：
Arimura, Noboru;Ki-i, Yuya;Maruyama, Ikuro
High-mobility group box 1 （HMGB1）蛋白是一种多功能性蛋白，主要存在于细胞核内，并由濒死细胞和/或活化的免疫细胞向细胞外释放。尽管细胞外HMGB1被认为是组织损伤的典型危险信号，并与多种疾病有关，但其与眼部疾病的相关性大多尚不清楚。为了确定HMGB1是否参与视网膜脱离（RD）的发病机制，包括光感受器变性，我们研究了HMGB1在体外过度氧化应激诱导的视网膜细胞死亡和RD诱导的光感受器变性大鼠模型中的表达和释放。此外，我们评估了人眼视网膜色素上皮（RPE）细胞系中HMGB1和单核细胞趋化蛋白1 （MCP-1）的玻璃体浓度。我们还探讨了重组HMGB1在人视网膜色素上皮（RPE）细胞系中的趋化活性。结果表明，视网膜细胞中的核HMGB1在死亡应激的作用下增强，其表达上调似乎是细胞存活所必需的，而HMGB1的细胞外释放不仅在体外视网膜细胞死亡中明显，而且在体内RD大鼠模型中也很明显。在体外实验中，重组HMGB1通过细胞外信号调节的激酶依赖机制诱导RPE细胞迁移。我们的研究结果表明HMGB1是一种至关重要的核蛋白，并作为视网膜组织损伤的危险信号释放。细胞外HMGB1可能是RD的重要介质，可能作为RPE细胞迁移的趋化因子，导致眼部病理性伤口愈合反应。
High-mobility group box 1 (HMGB1) protein is a multifunctional protein, which is mainly present in the nucleus and is released extracellularly by dying cells and/or activated immune cells. Although extracellular HMGB1 is thought to be a typical danger signal of tissue damage and is implicated in diverse diseases, its relevance to ocular diseases is mostly unknown. To determine whether HMGB1 contributes to the pathogenesis of retinal detachment (RD), which involves photoreceptor degeneration, we investigated the expression and release of HMGB1 both in a retinal cell death induced by excessive oxidative stress in vitro and in a rat model of RD-induced photoreceptor degeneration in vivo. In addition, we assessed the vitreous concentrations of HMGB1 and monocyte chemoattractant protein 1 (MCP-1) in human eyes with RD. We also explored the chemotactic activity of recombinant HMGB1 in a human retinal pigment epithelial (RPE) cell line. The results show that the nuclear HMGB1 in the retinal cell is augmented by death stress and upregulation appears to be required for cell survival, whereas extracellular release of HMGB1 is evident not only in retinal cell death in vitro but also in the rat model of RD in vivo. Furthermore, the vitreous level of HMGB1 is significantly increased and is correlated with that of MCP-1 in human eyes with RD. Recombinant HMGB1 induced RPE cell migration through an extracellular signal-regulated kinase-dependent mechanism in vitro. Our findings suggest that HMGB1 is a crucial nuclear protein and is released as a danger signal of retinal tissue damage. Extracellular HMGB1 might be an important mediator in RD, potentially acting as a chemotactic factor for RPE cell migration that would lead to an ocular pathological wound-healing response.