Potential role for S100A4 in the disruption of the blood–brain barrier in collagen-induced arthritic mice, an animal model of rheumatoid arthritis
Potential role for S100A4 in the disruption of the blood–brain barrier in collagen-induced arthritic mice, an animal model of rheumatoid arthritis
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DOI：
10.1016/j.neuroscience.2011.05.044
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发表时间：
2011-08
期刊：
影响因子：
3.3
通讯作者：
T. Nishioku;K. Furusho;A. Tomita;H. Ohishi;S. Dohgu;H. Shuto;A. Yamauchi;Y. Kataoka
中科院分区：
文献类型：
--
作者：
T. Nishioku;K. Furusho;A. Tomita;H. Ohishi;S. Dohgu;H. Shuto;A. Yamauchi;Y. Kataoka
类风湿性关节炎（RA）是一种与关节慢性炎症相关的自身免疫性疾病。风湿性关节炎已被证明会增加心脑血管疾病的发病率和死亡率。我们最近报道了胶原诱导关节炎（CIA）小鼠的脑血管通透性增加，这是一种RA动物模型。S100A4是S100家族的一员，在RA患者的滑液和血浆中表达上调。本研究旨在评估S100A4在CIA小鼠血脑屏障（BBB）功能障碍中的介导作用。采用ⅱ型胶原免疫诱导小鼠CIA。通过测量对照组和CIA小鼠脑内荧光素钠（Na-F）水平来评估脑血管通透性。采用酶联免疫吸附法（ELISA）测定对照组和CIA小鼠血清S100A4浓度。CIA小鼠脑内Na-F积累和血清中S100A4水平升高。血清S100A4水平升高与脑血管内皮对Na-F的高通透性密切相关。我们利用小鼠脑毛细血管内皮细胞（MBECs）研究S100A4是否诱导血脑屏障功能障碍。S100A4降低了MBECs的跨内皮电阻，增加了Na-F的通透性。S100A4降低了紧密连接蛋白occludin的表达，并刺激了MBECs中p53的表达。这些发现表明，S100A4通过降低occludin的表达水平（至少部分通过p53）增加MBECs的细胞旁通透性。目前的研究强调了S100A4在RA患者脑血管疾病的血脑屏障功能障碍中的潜在作用。
Rheumatoid arthritis (RA) is an autoimmune disease associated with chronic inflammation of the joints. RA has been shown to increase the morbidity of and mortality due to cardiovascular and cerebrovascular diseases. We recently reported that cerebrovascular permeability was increased in mice with collagen-induced arthritis (CIA), an animal model of RA. S100A4, a member of the S100 family, is up-regulated in synovial fluid and plasma from RA patients. This study was aimed at evaluating a role of S100A4 in the mediation of blood–brain barrier (BBB) dysfunction in CIA mice. CIA was induced by immunization with type II collagen in mice. Cerebrovascular permeability was assessed by measurement of sodium fluorescein (Na-F) levels in the brains of control and CIA mice. Serum S100A4 concentrations in control and CIA mice were measured by enzyme-linked immunosorbent assays (ELISA). Accumulation of Na-F in the brain and serum levels of S100A4 were increased in CIA mice. Increased S100A4 levels in the serum are closely correlated with hyperpermeability of the cerebrovascular endothelium to Na-F. We investigated whether S100A4 induces BBB dysfunction using mouse brain capillary endothelial cells (MBECs). S100A4 decreased the transendothelial electrical resistance and increased Na-F permeability in the MBECs. S100A4 reduced the expression of occludin, a tight junction protein, and stimulated p53 expression in MBECs. These findings suggest that S100A4 increases paracellular permeability of MBECs by decreasing expression levels of occludin, at least in part, via p53. The present study highlights a potential role for S100A4 in BBB dysfunction underlying cerebrovascular diseases in patients with RA.