Marneros Alexander G
Department of Dermatology, Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, 02129, Charlestown, MA, USA.
Adv Exp Med Biol. 2016;854:79-85. doi: 10.1007/978-3-319-17121-0_12.
The pathomechanisms that lead to age-related macular degeneration (AMD) are only partially understood. The NLRP3 inflammasome has been shown to be activated in the retinal pigment epithelium (RPE) in eyes with AMD. However, it is not known whether inflammasome activation is a cause or consequence of pathologic changes in AMD. A roadblock to defining the role of inflammasome activation and pathways that regulate it for AMD has been the lack of a mouse model that forms AMD-like pathologies in an age-dependent manner in which the role of the inflammasome can be investigated using genetic studies. We have recently identified such a mouse model, in which increased VEGF-A levels result in early degenerative changes of the RPE, followed by cardinal features of both nonexudative and neovascular AMD. Importantly, higher VEGF-A levels lead to increased oxidative damage and a sub-retinal inflammatory infiltrate that are associated with NLRP3 inflammasome activation in the RPE. Targeting the NLRP3 inflammasome inhibited AMD-like pathologies in these mice. These findings suggest that inhibiting the NLRP3 inflammasome or pathways that regulate it may provide novel therapeutic approaches for the treatment of both forms of AMD.
导致年龄相关性黄斑变性（AMD）的病理机制仅得到部分理解。已证明NLRP3炎性小体在患有AMD的眼睛的视网膜色素上皮（RPE）中被激活。然而，尚不清楚炎性小体激活是AMD病理变化的原因还是结果。由于缺乏一种能以年龄依赖性方式形成类似AMD病理的小鼠模型，在该模型中可以使用遗传学研究来探究炎性小体的作用，这一直是确定炎性小体激活及其调控途径在AMD中的作用的一个障碍。我们最近鉴定出了这样一种小鼠模型，其中VEGF-A水平升高导致RPE早期退行性变化，随后出现非渗出性和新生血管性AMD的主要特征。重要的是，较高的VEGF-A水平会导致氧化损伤增加和视网膜下炎性浸润，这与RPE中NLRP3炎性小体激活有关。靶向NLRP3炎性小体可抑制这些小鼠中的类似AMD的病理变化。这些发现表明，抑制NLRP3炎性小体或其调控途径可能为两种形式的AMD治疗提供新的治疗方法。
