Prostaglandin D2-mediated microglia/astrocyte interaction enhances astrogliosis and demyelination in twitcher
Prostaglandin D2-mediated microglia/astrocyte interaction enhances astrogliosis and demyelination in twitcher
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DOI：
10.1523/jneurosci.4531-05.2006
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发表时间：
2006-04-19
影响因子：
5.3
通讯作者：
Urade, Y
中科院分区：
文献类型：
--
作者：
Mohri, I;Taniike, M;Urade, Y
前列腺素（PG） D-2是众所周知的炎症介质。造血PGD合成酶（HPGDS）负责产生PGD(2)参与炎症反应。在神经炎症期间，包括脱髓鞘期间，通常观察到小胶质细胞激活和星形胶质细胞形成。利用人类克拉伯氏病的遗传脱髓鞘小鼠抽动器模型，我们发现在这些小鼠的大脑中，激活的小胶质细胞表达HPGDS，激活的星形胶质细胞表达PGD2的DP1受体。培养的小胶质细胞在HPGDS的作用下积极产生PGD2。培养的星形胶质细胞表达两种类型的PGD(2)受体DP1和DP2，并且在其各自的激动剂刺激任一受体后显示GFAP的产生增强。这些结果表明PGD(2)在小胶质细胞/星形胶质细胞相互作用中起重要作用。我们证明，使用HPGDS-或DP1-null抽搐小鼠，以及用HPGDS抑制剂HQL-79(4-苯并羟基-1-[3-（1h -四唑-5-基）-丙基]哌啶治疗的抽搐小鼠，阻断HPGDS/PGD(2)/DP信号通路，可显著抑制星形胶质细胞形成和脱髓鞘，并减少抽搐和痉挛。此外，我们发现HPGDS- null和hql -79处理的抽搐小鼠少突胶质细胞凋亡程度也有所降低。这些结果表明PGD2是抽搐小鼠对脱髓鞘病理反应增强的关键神经炎症分子。
Prostaglandin (PG) D-2 is well known as a mediator of inflammation. Hematopoietic PGD synthase (HPGDS) is responsible for the production of PGD(2) involved in inflammatory responses. Microglial activation and astrogliosis are commonly observed during neuro-inflammation, including that which occurs during demyelination. Using the genetic demyelination mouse twitcher, a model of human Krabbe's disease, we discovered that activated microglia expressed HPGDS and activated astrocytes expressed the DP1 receptor for PGD2 in the brain of these mice. Cultured microglia actively produced PGD2 by the action of HPGDS. Cultured astrocytes expressed two types of PGD(2) receptor, DP1 and DP2, and showed enhanced GFAP production after stimulation of either receptor with its respective agonist. These results suggest that PGD(2) plays an important role in microglia/astrocyte interaction. We demonstrated that the blockade of the HPGDS/PGD(2)/DP signaling pathway using HPGDS- or DP1-null twitcher mice, and twitcher mice treated with an HPGDS inhibitor, HQL-79 (4-benzhydryloxy-1-[3-(1H-tetrazol-5-yl)-propyl]piperidine), resulted in remarkable suppression of astrogliosis and demyelination, as well as a reduction in twitching and spasticity. Furthermore, we found that the degree of oligodendroglial apoptosis was also reduced in HPGDS- null and HQL-79-treated twitcher mice. These results suggest that PGD2 is the key neuroinflammatory molecule that heightens the pathological response to demyelination in twitcher mice.