Microglia-derived IL-1β promotes chemokine expression by Müller cells and RPE in focal retinal degeneration.
Microglia-derived IL-1β promotes chemokine expression by Müller cells and RPE in focal retinal degeneration.
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DOI：
10.1186/s13024-017-0175-y
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发表时间：
2017-04-24
影响因子：
15.1
通讯作者：
Rutar M
中科院分区：
文献类型：
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作者：
Natoli R;Fernando N;Madigan M;Chu-Tan JA;Valter K;Provis J;Rutar M
趋化因子信号传导是视网膜炎症过程中白细胞归巢所必需的，并且与诸如年龄相关性黄斑变性（AMD）的疾病的发病机制相关。在此，我们探讨白细胞介素-1 β（IL-1β）在光氧化视网膜损伤过程中调节AMD相关趋化因子Ccl 2、Cxcl 1和Cxcl 10的作用，以及对视网膜外巨噬细胞积聚和光感受器死亡的影响。使用siRNA或抗体中和进行视网膜IL-1β表达的抑制，在光氧化损伤之前将其玻璃体内注射到SD大鼠中。使用qPCR和原位杂交评估IL-1β、Ccl 2、Cxcl 1和Cxcl 10基因表达和定位的变化，同时使用IBA 1的免疫组织化学检测视网膜巨噬细胞的募集。使用TUNEL测定光感受器细胞死亡的水平。光氧化损伤后IL-1β和炎性小体相关基因表达增加，视网膜外层浸润的小胶质细胞中检测到IL-1β蛋白。这与Ccl 2、Cxcl 1和Cxcl 10的表达增加有关。玻璃体内IL-1β抑制剂抑制损伤后的趋化因子表达，并减少巨噬细胞积聚和感光细胞死亡。此外，在Müller和RPE细胞培养物中，以及在体内，当用IL-1β刺激时，Ccl 2、Cxcl 1和Cxcl 10不同程度地上调，体内检测到巨噬细胞蓄积增加。IL-1β由视网膜小胶质细胞和巨噬细胞产生，并促进视网膜变性中Müller细胞和RPE的趋化因子表达。靶向IL-1β可能被证明在广泛抑制视网膜营养不良（如AMD）中趋化因子介导的炎症方面有效。
Chemokine signalling is required for the homing of leukocytes during retinal inflammation, and is associated with pathogenesis of diseases such as age-related macular degeneration (AMD). Here, we explore the role of interleukin-1β (IL-1β) in modulating AMD-associated chemokines Ccl2, Cxcl1, and Cxcl10 during photo-oxidative retinal damage, and the effect on both the accumulation of outer-retinal macrophages, and death of photoreceptors. Inhibition of retinal IL-1β expression was performed using either siRNA or antibody neutralisation, which was intravitreally injected in SD rats prior to photo-oxidative damage. Changes in the expression and localisation of Il-1β, Ccl2, Cxcl1 and Cxcl10 genes were assessed using qPCR and in situ hybridisation, while the recruitment of retinal macrophages was detected using immunohistochemistry for IBA1. Levels of photoreceptor cell death were determined using TUNEL. Photo-oxidative damage elevated the expression of Il-1β and inflammasome-related genes, and IL-1β protein was detected in microglia infiltrating the outer retina. This was associated with increased expression of Ccl2, Cxcl1, and Cxcl10. Intravitreal IL-1β inhibitors suppressed chemokine expression following damage and reduced macrophage accumulation and photoreceptor death. Moreover, in Müller and RPE cell cultures, and in vivo, Ccl2, Cxcl1 and Cxcl10 were variously upregulated when stimulated with IL-1β, with increased macrophage accumulation detected in vivo. IL-1β is produced by retinal microglia and macrophages and promotes chemokine expression by Müller cells and RPE in retinal degeneration. Targeting IL-1β may prove efficacious in broadly suppressing chemokine-mediated inflammation in retinal dystrophies such as AMD.