The High-Mobility Group Box-1 Nuclear Factor Mediates Retinal Injury after Ischemia Reperfusion
The High-Mobility Group Box-1 Nuclear Factor Mediates Retinal Injury after Ischemia Reperfusion
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DOI：
10.1167/iovs.11-7793
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发表时间：
2011-09-01
影响因子：
4.4
通讯作者：
Ivanov, Dmitry
中科院分区：
文献类型：
--
作者：
Dvoriantchikova, Galina;Hernandez, Eleut;Ivanov, Dmitry
目的。高迁移率族蛋白B1(HMGB1)从坏死细胞中释放出来，诱导炎症反应。虽然HMGB1与脑缺血再灌注损伤有关，但其在视网膜IR损伤中的作用尚不清楚。在此，作者提供了HMGB1参与视网膜缺血再灌注损伤的证据。方法通过单眼高眼压诱导视网膜IR损伤，并分析再灌注后24小时玻璃体液中HMGB1的水平。为探讨HMGB1释放的功能意义，分别用中和抗HMGB1抗体或重组HMGB1蛋白处理缺血视网膜和正常视网膜。为了阐明HMGB1在哪种细胞类型中发挥作用，我们用HMGB1处理原代培养的视网膜神经节细胞(RGC)和胶质细胞RGC共培养。为了阐明HMGB1诱导的视网膜缺血效应的下游信号通路，采用晚期糖基化终产物受体(RAGE)缺陷小鼠(RageKO)。用中和抗体抑制HMGB1活性可显著减轻IR后视网膜的损伤，而用HMGB1处理视网膜或视网膜细胞则导致RGCs的丢失。RageKO与野生型小鼠比较显示，再灌注后24小时促炎基因表达显著减少，7天后神经节细胞层神经元存活率显著增加。结论这些结果提示视网膜IR损伤后HMGB1水平升高和Rage信号转导参与了视网膜IR损伤后的神经毒性。(投资眼科VS科学。2011年；52：7187-7194)doi：10.1167/iovs.11-7793
PURPOSE. High-mobility group protein B1 (Hmgb1) is released from necrotic cells and induces an inflammatory response. Although Hmgb1 has been implicated in ischemia/reperfusion (IR) injury of the brain, its role in IR injury of the retina remains unclear. Here, the authors provide evidence that Hmgb1 contributes to retinal damage after IR.METHODS. Retinal IR injury was induced by unilateral elevation of intraocular pressure and the level of Hmgb1 in vitreous humor was analyzed 24 hours after reperfusion. To test the functional significance of Hmgb1 release, ischemic or normal retinas were treated with the neutralizing anti-Hmgb1 antibody or recombinant Hmgb1 protein respectively. To elucidate in which cell type Hmgb1 exerts its effect, primary retinal ganglion cell (RGC) cultures and glia RGC cocultures were treated with Hmgb1. To clarify the downstream signaling pathways involved in Hmgb1-induced effects in the ischemic retina, receptor for advanced glycation end products (Rage)-deficient mice (RageKO) were used.RESULTS. Hmgb1 is accumulated in the vitreous humor 24 hours after IR. Inhibition of Hmgb1 activity with neutralizing antibody significantly decreased retinal damage after IR, whereas treatment of retinas or retinal cells with Hmgb1 induced a loss of RGCs. The analysis of RageKO versus wild-type mice showed significantly reduced expression of proinflammatory genes 24 hours after reperfusion and significantly increased survival of ganglion cell layer neurons 7 days after IR injury.CONCLUSIONS. These results suggest that an increased level of Hmgb1 and signaling via the Rage contribute to neurotoxicity after retinal IR injury. (Invest Ophthalmol Vis Sci. 2011;52:7187-7194) DOI:10.1167/iovs.11-7793