Oxidative stress, innate immunity, and age-related macular degeneration.
Oxidative stress, innate immunity, and age-related macular degeneration.
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氧化应激、先天免疫和年龄相关性黄斑变性
DOI：
10.3934/molsci.2016.2.196
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发表时间：
2016
影响因子：
1.4
通讯作者：
Xiao X
中科院分区：
文献类型：
--
作者：
Shaw PX;Stiles T;Douglas C;Ho D;Fan W;Du H;Xiao X
视网膜相关性黄斑变性（AMD）是影响全世界数千万老年人的视力丧失的主要原因。早期AMD的特征在于出现软性玻璃疣，以及视网膜色素上皮（RPE）中的色素改变。这些柔软、融合的玻璃疣可以进展成两种形式的晚期AMD：地图状萎缩（GA，或干性AMD）或脉络膜新生血管形成（CNV，或湿性AMD）。两种形式的AMD在中心视力丧失方面导致相似的临床进展。发展早期AMD的确切机制，以及导致疾病进展到晚期的触发因素，在很大程度上仍然是未知的。然而，存在显著的证据表明遗传和环境因素的复杂相互作用是AMD进展的原因。已经发现多个基因和/或单核苷酸多态性（SNP）与AMD相关，包括参与补体途径、脂质代谢和细胞外基质（ECM）重塑的各种基因。在已知的疾病风险遗传因素中，CFH Y 402 H和HTRA 1/ARMS多态性占AMD遗传风险的50%以上。从环境角度来看，氧化应激在许多衰老疾病中发挥着关键作用，包括心血管疾病、癌症、阿尔茨海默病和AMD。由于暴露于阳光和高氧浓度，眼睛中的氧化应激负荷高于其他组织，这可能会因吸烟等额外的氧化应激因素而进一步复杂化。越来越多的证据表明，通过高风险基因型引起的先天免疫系统的功能异常可能通过改变眼睛中的炎症稳态，特别是在氧化产物的处理中，导致AMD的发病机制。由于在非病理性情况下，尽管存在相对丰富的潜在炎症分子，但眼睛仍保持低水平的炎症，因此我们先前假设通过先天免疫系统对炎症的严格稳态控制可能对于避免疾病进展至关重要。然而，炎症的多种潜在触发物的存在导致敏感的平衡，其中其扰动将随后改变视网膜的炎症状态，导致慢性炎症和病理进展的状态。在这篇综述中，我们将突出背景文献周围的已知的遗传和环境因素AMD的风险，以及讨论这些因素的潜在机制的相互作用，导致疾病的发病机制，特别强调微妙的控制炎症稳态和先天免疫系统在这个过程中的中心地位。
Age-related macular degeneration (AMD) is a leading cause of vision loss affecting tens of millions of elderly worldwide. Early AMD is characterized by the appearance of soft drusen, as well as pigmentary changes in the retinal pigment epithelium (RPE). These soft, confluent drusen can progress into two forms of advanced AMD: geographic atrophy (GA, or dry AMD) or choroidal neovascularization (CNV, or wet AMD). Both forms of AMD result in a similar clinical progression in terms of loss of central vision. The exact mechanism for developing early AMD, as well as triggers responsible for progressing to advanced stage of disease, is still largely unknown. However, significant evidence exists demonstrating a complex interplay of genetic and environmental factors as causes of AMD progression. Multiple genes and/or single nucleotide polymorphisms (SNPs) have been found associated with AMD, including various genes involved in the complement pathway, lipid metabolism and extracellular matrix (ECM) remodeling. Of the known genetic contributors to disease risk, the CFH Y402H and HTRA1/ARMS polymorphisms contribute to more than 50% of the genetic risk for AMD. Environmentally, oxidative stress plays a critical role in many aging diseases including cardiovascular disease, cancer, Alzheimer’s disease and AMD. Due to the exposure to sunlight and high oxygen concentration, the oxidative stress burden is higher in the eye than other tissues, which can be further complicated by additional oxidative stressors such as smoking. Increasingly, evidence is accumulating suggesting that functional abnormalities of the innate immune system incurred via high risk genotypes may be contributing to the pathogenesis of AMD by altering the inflammatory homeostasis in the eye, specifically in the handling of oxidation products. As the eye in non-pathological instances maintains a low level of inflammation despite the presence of a relative abundance of potentially inflammatory molecules, we have previously hypothesized that the tight homeostatic control of inflammation via the innate immune system is likely critical for avoidance of disease progression. However, the presence of a multitude of potential triggers of inflammation results in a sensitive balance in which perturbations thereof would subsequently alter the inflammatory state of the retina, leading to a state of chronic inflammation and pathologic progression. In this review, we will highlight the background literature surrounding the known genetic and environmental contributors to AMD risk, as well as a discussion of the potential mechanistic interplay of these factors that lead to disease pathogenesis with particular emphasis on the delicate control of inflammatory homeostasis and the centrality of the innate immune system in this process.