AMD 相关的 HTRA1 变体不会影响小胶质细胞中的 TGF-β 信号转导。
AMD-Associated HTRA1 Variants Do Not Influence TGF-β Signaling in Microglia.
机构信息
Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
Institute for Dental Research and Oral Musculoskeletal Biology and Center for Biochemistry, University of Cologne, Cologne, Germany.
出版信息
Adv Exp Med Biol. 2019;1185:3-7. doi: 10.1007/978-3-030-27378-1_1.
Genetic variants of high-temperature requirement A serine peptidase 1 (HTRA1) and age-related maculopathy susceptibility 2 (ARMS2) are associated with age-related macular degeneration (AMD). One HTRA1 single nucleotide polymorphism (SNP) is situated in the promotor region (rs11200638) resulting in increased expression, while two synonymous SNPs are located in exon 1 (rs1049331:C > T, rs2293870:G > T). HtrA1 is known to inhibit transforming growth factor-β (TGF-β) signaling, a pathway regulating quiescence of microglia, the resident immune cells of the brain and retina. Microglia-mediated immune responses contribute to AMD pathogenesis. It is currently unclear whether AMD-associated HTRA1 variants influence TGF-β signaling and microglia phenotypes. Here, we show that an HtrA1 isoform carrying AMD-associated SNPs in exon 1 exhibits increased proteolytic activity. However, when incubating TGF-β-treated reactive microglia with HtrA1 protein variants, neither the wildtype nor the SNP-associated isoforms changed microglia activation in vitro.
HTRA1 基因和 ARMS2 基因的遗传变异与年龄相关性黄斑变性（AMD）有关。HTRA1 基因的一个单核苷酸多态性（SNP）位于启动子区域（rs11200638），导致表达增加，而两个同义 SNP 位于外显子 1（rs1049331：C>T，rs2293870：G>T）。HtrA1 已知可抑制转化生长因子-β（TGF-β）信号通路，该通路调节小胶质细胞的静止状态，小胶质细胞是大脑和视网膜的固有免疫细胞。小胶质细胞介导的免疫反应有助于 AMD 的发病机制。目前尚不清楚与 AMD 相关的 HTRA1 变体是否会影响 TGF-β 信号通路和小胶质细胞表型。在这里，我们表明携带外显子 1 中与 AMD 相关 SNP 的 HtrA1 同种型表现出增加的蛋白水解活性。然而，当在用 TGF-β 处理的反应性小胶质细胞中孵育 HtrA1 蛋白变体时，野生型和 SNP 相关同种型均未改变体外小胶质细胞的激活。
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