Prostaglandin D_2 is a key molecule for neuroinflammation in the demyelinating diseases

前列腺素 D_2 是脱髓鞘疾病中神经炎症的关键分子

• 批准号: 17591085
• 负责人: TANIIKE Masako
• 金额: $ 2.24万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591085/
• 关键词: Demyelination; Prostaglandin D2; Neuroinflammation; Microglia; Astrocyte; Prostaglandin D synthase; Neuropathology; Apoptois; 脱髄

Prostaglandin (PG) D2 is well known as an inflammatory mediator. The biological actions of PGD_2 are elicited through binding to DP_1 or DP_2 receptor. Hematopoi_etic PGD synthase (HPGDS) is responsible for the production of PGD_2,and is expressed in microglia in CNS. (Mohri et al.2003). The twitcher mouse (GALC^<twi/twi>) is an authentic animal model of human globoid cell leukodystrophy (Krabbe's disease) resulting from the deficiency of galactosylceramidase. In this model, the demyelination is caused by the apoptosis of oligodendrocytes (OLs) after postnatal day (PND) 30,and is always accompanied by the activation of microglia and gliosis throughout the brain. In this study, we found that HPGDS expression was progressively upregulated in activated microglia in the GALC^<twi/twi> brain. This upregulation was accompanied by the induction of the DP_1 receptor in hypertrophic astrocytes located close to HPGDS^+ microglia. Using primary culture of glial cells, we demonstrated that activated microglia produced large amount of PGD_2 by HPGDS and that astrocytes expressed both DP_1 and DP_2 receptors and were activated by PGD_2. Furthermore, by using HPGDS- or DP_1-deficient GALC^<twi/twi> mice and GALC^<twi/twi> mice treated with an HPGDS-inhibitor, we found that the blockade of the HPGDS/PGD_2/DP signaling pathway resulted in the suppression of gliosis and oligodendroglial apoptosis. This is the first example of a PGD_2-mediated microglia/astrocyte interaction in neuroinflammation.

前列腺素（PG）D2是众所周知的炎症介质。PGD_2的生物学作用是通过与DP_1或DP_2受体结合而发挥的。造血PGD合成酶（HPGDS）是负责PGD_2的合成，在中枢神经系统的小胶质细胞中表达。（Mohri等人，2003年）。抽搐小鼠（GALC^<twi/twi>）是由半乳糖基神经酰胺酶缺乏引起的人球状细胞脑白质营养不良（克拉伯病）的真实动物模型。在该模型中，脱髓鞘是由出生后30天（PND）后的少突胶质细胞（OLs）凋亡引起的，并且总是伴随着整个脑中的小胶质细胞活化和胶质细胞增生。在这项研究中，我们发现HPGDS表达在GALC^<twi/twi>脑中的活化小胶质细胞中进行性上调。在HPGDS^+小胶质细胞附近的肥大星形胶质细胞中，这种上调伴随着DP_1受体的诱导。利用原代培养的胶质细胞，我们证实了HPGDS激活的小胶质细胞产生大量的PGD_2，而星形胶质细胞表达DP_1和DP_2受体，并被PGD_2激活。此外，通过使用HPGDS或DP_1缺陷的GALC^<twi/twi>小鼠和用HPGDS抑制剂处理的GALC^<twi/twi>小鼠，我们发现HPGDS/PGD_2/DP信号通路的阻断导致胶质增生和少突胶质细胞凋亡的抑制。这是PGD_2介导的小胶质细胞/星形胶质细胞在神经炎症中相互作用的第一个例子。

项目成果

Early induction of neuronal lipocalin-type prostaglandin D synthase after hypoxic-ischemic injury in developing brains

• DOI: 10.1016/j.neulet.2007.04.016
• 发表时间: 2007-06
• 期刊: Neuroscience Letters
• 影响因子: 2.5
• 作者: Hidetoshi Taniguchi;I. Mohri;Hitomi Okabe-Arahori;T. Kanekiyo;Kuriko Kagitani-Shimono;Kazuko Wada;Y. Urade;M. Nakayama;K. Ozono;M. Taniike

Prostaglandin D2-mediated microglia/astrocyte interaction enhances astrogliosis and demyelination in twitcher

• DOI: 10.1523/jneurosci.4531-05.2006
• 发表时间: 2006-04-19
• 期刊: JOURNAL OF NEUROSCIENCE
• 影响因子: 5.3
• 作者: Mohri, I;Taniike, M;Urade, Y
• 通讯作者: Urade, Y

Hypersomnolence and increased REM sleep with low cerebrospinal fluid hypocretin level in a patient after removal of craniopharyngioma

• DOI: 10.1016/j.sleep.2005.04.002
• 发表时间: 2005-11-01
• 期刊: SLEEP MEDICINE
• 影响因子: 4.8
• 作者: Tachibana, N;Taniike, M;Nishino, S
• 通讯作者: Nishino, S

Lipocalin-type prostaglandin D synthase (beta-trace) is upregulated in the alphaB-crystallin-positive oligodendrocytes and astrocytes in the chronic multiple sclerosis.

在慢性多发性硬化症中，脂质运载蛋白型前列腺素 D 合酶（β-痕量）在 αB-晶状体蛋白阳性少突胶质细胞和星形胶质细胞中上调。

• 发表时间: 2006
• 期刊: Neuropathol Appl Neurobiol 32(1)
• 作者: Kagitani-Shimono K;Mohri I;Oda H;Ozono K;Suzuki K;Urade Y;Taniike M.
• 通讯作者: Taniike M.

Novel mutation of gene coding for glial fibrillary acidic protein in a Japanese patient with Alexander disease

日本亚历山大病患者胶质纤维酸性蛋白编码基因的新突变

• 发表时间: 2006
• 期刊: Brain Dev 28・1
• 作者: Kawai;M;Sakai;N. et al.(8)
• 通讯作者: N. et al.(8)