PDF(Pubmed)
Abstract：
Ischemia-induced retinopathy is a hallmark finding of common visual disorders including diabetic retinopathy (DR) and central retinal artery and vein occlusions. Treatments for ischemic retinopathies fail to improve clinical outcomes and the design of new therapies will depend on understanding the underlying disease mechanisms. Histone deacetylases (HDACs) are an enzyme class that removes acetyl groups from histone and non-histone proteins, thereby regulating gene expression and protein function. HDACs have been implicated in retinal neurovascular injury in preclinical studies in which nonspecific HDAC inhibitors mitigated retinal injury. Histone deacetylase 3 (HDAC3) is a class I histone deacetylase isoform that plays a central role in the macrophage inflammatory response. We recently reported that myeloid cells upregulate HDAC3 in a mouse model of retinal ischemia-reperfusion (IR) injury. However, whether this cellular event is an essential contributor to retinal IR injury is unknown. In this study, we explored the role of myeloid HDAC3 in ischemia-induced retinal neurovascular injury by subjecting myeloid-specific HDAC3 knockout (M-HDAC3 KO) and floxed control mice to retinal IR. The M-HDAC3 KO mice were protected from retinal IR injury as shown by the preservation of inner retinal neurons, vascular integrity, and retinal thickness. Electroretinography confirmed that this neurovascular protection translated to improved retinal function. The retinas of M-HDAC3 KO mice also showed less proliferation and infiltration of myeloid cells after injury. Interestingly, myeloid cells lacking HDAC3 more avidly engulfed apoptotic cells in vitro and after retinal IR injury in vivo compared to wild-type myeloid cells, suggesting that HDAC3 hinders the reparative phagocytosis of dead cells, a process known as efferocytosis. Further mechanistic studies indicated that although HDAC3 KO macrophages upregulate the reparative enzyme arginase 1 (A1) that enhances efferocytosis, the inhibitory effect of HDAC3 on efferocytosis is not solely dependent on A1. Finally, treatment of wild-type mice with the HDAC3 inhibitor RGFP966 ameliorated the retinal neurodegeneration and thinning caused by IR injury. Collectively, our data show that HDAC3 deletion enhances macrophage-mediated efferocytosis and protects against retinal IR injury, suggesting that inhibiting myeloid HDAC3 holds promise as a novel therapeutic strategy for preserving retinal integrity after ischemic insult.
摘要：
缺血诱发的视网膜病变是常见视觉障碍的标志，包括糖尿病性视网膜病变（DR）和中央视网膜动脉和静脉阻塞。缺血性视网膜病变的治疗无法改善临床结果，新疗法的设计将取决于了解潜在的疾病机制。组蛋白脱乙酰酶（HDAC）是一种从组蛋白和非组蛋白中去除乙酰基的酶类，从而调节基因表达和蛋白质功能。在非特异性HDAC抑制剂减轻视网膜损伤的临床前研究中，HDAC与视网膜神经血管损伤有关。组蛋白脱乙酰酶3（HDAC3）是I类组蛋白脱乙酰酶同工型，在巨噬细胞炎症反应中起重要作用。我们最近报道了在视网膜缺血再灌注（IR）损伤的小鼠模型中，骨髓细胞上调HDAC3。然而,该细胞事件是否是视网膜IR损伤的重要原因尚不清楚.在这项研究中,我们通过对髓样特异性HDAC3敲除(M-HDAC3KO)和对照小鼠进行视网膜IR检测,探讨了髓样HDAC3在缺血诱导的视网膜神经血管损伤中的作用.保护M-HDAC3KO小鼠免受视网膜IR损伤，如保留内部视网膜神经元所示，血管完整性,和视网膜厚度。视网膜电描记术证实这种神经血管保护作用可改善视网膜功能。M-HDAC3KO小鼠的视网膜在损伤后也显示出较少的骨髓细胞增殖和浸润。有趣的是,与野生型骨髓细胞相比，缺乏HDAC3的骨髓细胞在体外和体内视网膜IR损伤后更强烈地吞噬凋亡细胞，这表明HDAC3阻碍了死亡细胞的修复性吞噬作用，一个被称为红细胞增多的过程。进一步的机制研究表明，尽管HDAC3KO巨噬细胞上调了增强细胞增殖的修复酶精氨酸酶1（A1），HDAC3对细胞增殖的抑制作用并不仅仅依赖于A1。最后,用HDAC3抑制剂RGPP966治疗野生型小鼠改善了由IR损伤引起的视网膜神经变性和变薄。总的来说，我们的数据显示，HDAC3缺失增强巨噬细胞介导的细胞增生，并防止视网膜IR损伤，提示抑制髓样HDAC3有望成为缺血性损伤后保留视网膜完整性的新型治疗策略.
