Endogenous aggregates of amyloidogenic cystatin C variant are removed by THP-1 cells in vitro and induce differentiation and a proinflammatory response
Endogenous aggregates of amyloidogenic cystatin C variant are removed by THP-1 cells in vitro and induce differentiation and a proinflammatory response
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DOI：
10.1016/j.neurobiolaging.2012.11.012
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发表时间：
2013-05-01
影响因子：
4.2
通讯作者：
Petersen, Petur Henry
中科院分区：
文献类型：
--
作者：
Jonsdottir, Gudrun;Ingolfsdottir, Indiana Elin;Petersen, Petur Henry
人类胱抑素C基因突变导致家族性脑淀粉样血管病。这种疾病被称为“冰岛型遗传性淀粉样变性脑出血”或“遗传性胱抑素C淀粉样血管病”。突变的胱抑素C蛋白在中枢神经系统内形成聚集体和淀粉样蛋白，几乎完全与血管系统有关。目前尚不清楚免疫细胞是否能够清除突变的胱抑素C蛋白聚集体。体外突变的胱抑素C蛋白聚集体，无论是在溶液中还是在玻璃表面上干燥，都诱导与底物的粘附，分化THP-1单核细胞系，并导致促炎反应。聚集体也被THP-1细胞和THP-1衍生的巨噬细胞所吸收。这些反应与其他淀粉样蛋白物种（如β淀粉样蛋白和amylin）诱导的反应相同，这支持了所有淀粉样蛋白由于共同的结构基序而具有毒性的模型。体外突变型胱抑素C蛋白聚集体诱导的促炎反应提示血管炎症在冰岛型淀粉样变性遗传性脑出血中起重要作用。体外合成的胱抑素C蛋白聚集体可能比体外生成的聚集体或补充体外材料更好地模拟细胞行为。(C) 2013爱思唯尔公司版权所有。
A mutation in the human cystatin C gene leads to familial cerebral amyloid angiopathy. This disease is known as "hereditary cerebral hemorrhage with amyloidosis-Icelandic type" or "hereditary cystatin C amyloid angiopathy." The mutant cystatin C protein forms aggregates and amyloid, within the central nervous system almost exclusively in connection with the vascular system. It was not known whether immune cells could remove mutant cystatin C protein aggregates. Ex vivo mutant cystatin C protein aggregates, both in solution and dried onto a glass surface, induced adhesion to the substrate, differentiated the THP-1 monocyte cell line and led to a proinflammatory response. Aggregates were also taken up by both THP-1 cells and THP-1 derived macrophages. These are the same responses induced by other amyloidogenic protein species, such as amyloid beta protein and amylin, supporting the model of all amyloidogenic proteins being toxic due to common structural motifs. Proinflammatory response induced by the ex vivo mutant cystatin C protein aggregates suggests that vascular inflammation plays an important role in hereditary cerebral hemorrhage with amyloidosis-Icelandic type. Ex vivo protein aggregates of cystatin C might better model cellular behavior than in vitro-generated aggregates or supplement in vitro material. (C) 2013 Elsevier Inc. All rights reserved.