CFH Y402H polymorphism and the complement activation product C5a: effects on NF-κB activation and inflammasome gene regulation
CFH Y402H polymorphism and the complement activation product C5a: effects on NF-κB activation and inflammasome gene regulation
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DOI：
10.1136/bjophthalmol-2015-307213
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发表时间：
2016-05-01
影响因子：
4.1
通讯作者：
Matsubara, Joanne A.
中科院分区：
文献类型：
--
作者：
Cao, Sijia;Wang, Jay Ching Chieh;Matsubara, Joanne A.
背景与目的补体因子H（CFH）基因Y 402 H多态性是老年性黄斑变性（AMD）的一个重要危险因素。补体激活产物和促炎细胞因子在系统水平上与这种多态性相关，但在基因型眼的外视网膜中的相关性知之甚少。在这里，我们探讨补体激活产物及其在核因子（NF）-κ B B激活和基因表达的NLRP 3 inflammasome pathway.Methods死后供体眼基因分型的CFH Y 402 H多态性和评估补体C3 a，C5 a，白细胞介素（IL）-18和肿瘤坏死因子（TNF）-α。在极化培养物中用C5 a或TNF-α刺激ARPE 19细胞的基底外侧。用报告细胞系评估NF-κ B活化。研究了炎性小体相关（NLRP 3、半胱天冬酶-1、IL-1 β和IL-18）和经典炎性（IL-6和IL-8）基因的基因表达。炎症产物IL-1 β和IL-18的分布进行了研究，在尸检供体眼AMD pathology.Results眼睛与纯合子的风险变异表现出较高水平的C5 a，IL-18和TNF-α在布鲁赫膜和脉络膜。C5 a促进NF-κ B活化和极化ARPE 19中IL-18的上调。TNF-α促进NF-κ B活化和caspase-1、IL-1 β、IL-18、IL-6和IL-8的基因表达，但下调NLRP 3。在地图状萎缩的眼睛，强烈的免疫反应性，观察炎症产物IL-1 β和IL-18与年龄匹配的controls.Conclusion的CFH Y 402 H的风险多态性可能有助于AMD的疾病过程中，通过增加补体和NF-κ B激活，和上调IL-18，炎症体激活的产物。
Background/aims The Y402H polymorphism in the complement factor H (CFH) gene is an important risk factor for age-related macular degeneration (AMD). Complement activation products and proinflammatory cytokines are associated with this polymorphism at the systemic level, but less is known of the associations in the outer retina of the genotyped eye. Here we investigate complement activation products and their role in nuclear factor (NF)-kappa B activation and gene expression of the NLRP3 inflammasome pathway.Methods Postmortem donor eyes were genotyped for the CFH Y402H polymorphism and assessed for complement C3a, C5a, interleukin (IL)-18 and tumour necrosis factor (TNF)-alpha. ARPE19 cells were stimulated basolaterally with C5a or TNF-alpha in polarised cultures. NF-kappa B activation was assessed with a reporter cell line. Gene expression of inflammasome-related (NLRP3, caspase-1, IL-1 beta and IL-18) and classic inflammatory (IL-6 and IL-8) genes was studied. The distribution of inflammasome products, IL-1 beta and IL-18, was studied in postmortem donor eyes with AMD pathologies.Results Eyes with the homozygous at-risk variant demonstrated higher levels of C5a, IL-18 and TNF-alpha in Bruch's membrane and choroid. C5a promoted NF-kappa B activation and upregulation of IL-18 in polarised ARPE19. TNF-alpha promoted NF-kappa B activation and gene expression of caspase-1, IL-1 beta, IL-18, IL-6 and IL-8, but downregulated NLRP3. In eyes with geographic atrophy, strong immunoreactivity was observed for inflammasome products IL-1 beta and IL-18 compared with age-matched controls.Conclusion The at-risk polymorphism of the CFH Y402H may contribute to AMD disease process through increased complement and NF-kappa B activation, and the upregulation of IL-18, a product of inflammasome activation.