Involvement of the Bradykinin B(1) Receptor in Microglial Activation: In Vitro and In Vivo Studies.
Involvement of the Bradykinin B(1) Receptor in Microglial Activation: In Vitro and In Vivo Studies.
复制标题
DOI：
10.3389/fendo.2017.00082
复制
发表时间：
2017
影响因子：
5.2
通讯作者：
Fleisher-Berkovich S
中科院分区：
文献类型：
--
作者：
Asraf K;Torika N;Danon A;Fleisher-Berkovich S
脑部炎症对阿尔茨海默病 (AD) 发病机制的重要性最近已被接受，目前认为脑部炎症会加剧 AD 病理。脑炎症的一个重要方面是小胶质细胞的招募和激活，这一过程称为小胶质细胞增生。特别是激肽和缓激肽 (BK)，是外周主要的促炎介质，尽管组成激肽系统的所有因子也已在大脑中得到描述。此外，研究表明，β 淀粉样蛋白 (Aβ) 肽（AD 斑块的组成部分）可增强激肽分泌并激活 BK 受体，从而刺激 Aβ 的产生。尽管如此，缓激肽在调节大脑炎症和 AD 中的作用尚不完全清楚。在本研究中，我们旨在体外研究缓激肽B1受体（B1R）和缓激肽B2受体（B2R）在调节小胶质细胞促炎因子分泌中的作用。此外，还研究了鼻内施用特定 B1R 和 B2R 拮抗剂对转基因 AD 小鼠大脑中 Aβ 负荷和小胶质细胞积累的影响。获得的数据显示，R-715（B1R 拮抗剂）和 HOE 140（B2R 拮抗剂）均不会改变小胶质细胞的活力。然而，R-715（而非 HOE 140）显着增加了脂多糖诱导的一氧化氮 (NO) 和肿瘤坏死因子-α (TNF-α) 的释放，以及 BV2 小胶质细胞中诱导型一氧化氮合酶的表达。拮抗剂均不会改变未刺激细胞中 NO 和 TNF-α 的产生。我们还表明，对 8 周龄 5X 家族性 AD 小鼠鼻内施用 R-715（而非 HOE 140）可增强皮质中淀粉样蛋白的负荷和小胶质细胞/巨噬细胞的积累。总之，我们提供的证据支持 B1R 在 AD 小鼠脑部炎症和淀粉样蛋白沉积调节中的作用，可能与小胶质细胞/巨噬细胞有关。需要进一步的研究来测试这种受体的调节是否可以作为 AD 的新治疗策略。
The importance of brain inflammation to Alzheimer’s disease (AD) pathogenesis has been accepted of late, with it currently being held that brain inflammation aggravates AD pathology. One important aspect of brain inflammation is the recruitment and activation of microglia, a process termed microgliosis. Kinins and bradykinin (BK), in particular, are major pro-inflammatory mediators in the periphery, although all of the factors comprising the kinin system have also been described in the brain. Moreover, it was shown that the amyloid β (Aβ) peptide (a component of AD plaques) enhances kinin secretion and activates BK receptors that can, in turn, stimulate Aβ production. Still, the role of bradykinin in modulating brain inflammation and AD is not completely understood. In this study, we aimed to investigate the roles of the bradykinin B1 receptor (B1R) and bradykinin B2 receptor (B2R) in regulating microglial secretion of pro-inflammatory factors in vitro. Furthermore, the effects of intranasal administration of specific B1R and B2R antagonists on Aβ burden and microglial accumulation in the brains of transgenic AD mice were studied. The data obtained show that neither R-715 (a B1R antagonist) nor HOE 140 (a B2R antagonist) altered microglial cell viability. However, R-715, but not HOE 140, markedly increased lipopolysaccharide-induced nitric oxide (NO) and tumor necrosis factor-alpha (TNF-α) release, as well as inducible nitric oxide synthase expression in BV2 microglial cells. Neither antagonist altered NO nor TNF-α production in non-stimulated cells. We also showed that intranasal administration of R-715 but not HOE 140 to 8-week-old 5X familial AD mice enhanced amyloid burden and microglia/macrophage accumulation in the cortex. To conclude, we provide evidence supporting a role of B1R in brain inflammation and in the regulation of amyloid deposition in AD mice, possibly with microglial/macrophage involvement. Further studies are required to test whether modulation of this receptor can serve as a novel therapeutic strategy for AD.