The prostaglandin E2 EP2 receptor accelerates disease progression and inflammation in a model of amyotrophic lateral sclerosis.
The prostaglandin E2 EP2 receptor accelerates disease progression and inflammation in a model of amyotrophic lateral sclerosis.
复制标题
前列腺素E2 EP2受体在肌萎缩性侧面硬化症模型中加速了疾病进展和炎症。
DOI：
10.1002/ana.21437
复制
发表时间：
2008-09
影响因子：
11.2
通讯作者：
Andreasson, Katrin
中科院分区：
文献类型：
--
作者：
Liang, Xibin;Wang, Qian;Shi, Ju;Lokteva, Ludmila;Breyer, Richard M.;Montine, Thomas J.;Andreasson, Katrin
炎症已成为肌萎缩侧索硬化症（ALS）人类和转基因模型疾病进展的重要因素。最近的研究表明，前列腺素 E2 EP2 受体是先天免疫中炎症氧化损伤的主要调节因子。我们在家族性 ALS 的 G93A 超氧化物歧化酶 (SOD) 模型中测试了 EP2 信号传导是否参与疾病发病机制。我们检查了缺乏 EP2 受体的 G93A SOD 小鼠的表型，并进行了免疫细胞化学、定量逆转录酶聚合酶链反应和 Western 分析，以确定该模型中 EP2 毒性的机制。 G93A SOD 小鼠的星形胶质细胞和小胶质细胞中的 EP2 受体被显着诱导，同时促炎酶和脂质过氧化的表达增加。在人类 ALS 中，腹侧脊髓星形胶质细胞中 EP2 受体免疫反应性上调。在衰老的 G93A SOD 小鼠中，前列腺素 E2 EP2 受体的基因缺失提高了运动强度并延长了生存期。 G93A SOD 小鼠中 EP2 受体的缺失导致促炎效应物的水平显着降低，包括环氧合酶-1、环氧合酶-2、诱导型一氧化氮合酶和 NADPH 氧化酶复合物的成分。在其他炎症模型中，包括先天免疫的脂多糖模型和淀粉样变性的 APPSwe-PS1ΔE9 模型，EP2 的缺失也减少了促炎基因的表达。这些数据表明，前列腺素 E2 信号通过 EP2 受体在突变 SOD 模型中发挥作用，更广泛地在炎症神经变性中发挥作用，调节促炎基因盒的表达。抑制 EP2 信号传导可能代表了一种下调神经退行性疾病炎症反应的新策略。
Inflammation has emerged as an important factor in disease progression in human and transgenic models of amyotrophic lateral sclerosis (ALS). Recent studies demonstrate that the prostaglandin E2 EP2 receptor is a major regulator of inflammatory oxidative injury in innate immunity. We tested whether EP2 signaling participated in disease pathogenesis in the G93A superoxide dismutase (SOD) model of familial ALS. We examined the phenotype of G93A SOD mice lacking the EP2 receptor and performed immunocytochemistry, quantitative reverse transcriptase polymerase chain reaction, and Western analyses to determine the mechanism of EP2 toxicity in this model. EP2 receptor is significantly induced in G93A SOD mice in astrocytes and microglia in parallel with increases in expression of proinflammatory enzymes and lipid peroxidation. In human ALS, EP2 receptor immunoreactivity was upregulated in astrocytes in ventral spinal cord. In aging G93A SOD mice, genetic deletion of the prostaglandin E2 EP2 receptor improved motor strength and extended survival. Deletion of the EP2 receptor in G93A SOD mice resulted in significant reductions in levels of proinflammatory effectors, including cyclooxygenase-1, cyclooxygenase-2, inducible nitric oxide synthase, and components of the NADPH oxidase complex. In alternate models of inflammation, including the lipopolysaccharide model of innate immunity and the APPSwe-PS1ΔE9 model of amyloidosis, deletion of EP2 also reduced expression of proinflammatory genes. These data suggest that prostaglandin E2 signaling via the EP2 receptor functions in the mutant SOD model and more broadly in inflammatory neurodegeneration to regulate expression of a cassette of proinflammatory genes. Inhibition of EP2 signaling may represent a novel strategy to downregulate the inflammatory response in neurodegenerative disease.
登录
查看更多内容
DOI：
10.1073/pnas.0502552102
发表时间：
2005-07-12
影响因子：
11.1
作者：
Li, JR;Baud, O;Rosenberg, PA
通讯作者：
Rosenberg, PA
影响因子：
3.1
作者：
Liang, X.;Wu, L.;Andreasson, K.
通讯作者：
Andreasson, K.
影响因子：
158.5
作者：
in 't Veld, BA;Ruitenberg, A;Stricker, BHC
通讯作者：
Stricker, BHC
影响因子：
56.9
作者：
Kim, SF;Huri, DA;Snyder, SH
通讯作者：
Snyder, SH
影响因子：
11.2
作者：
Cudkowicz, Merit E.;Shefner, Jeremy M.;Drachman, Daniel B.
通讯作者：
Drachman, Daniel B.