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

前列腺素（PG） D2是众所周知的炎症介质。PGD_2通过与DP_1或DP_2受体结合而发挥生物活性。造血PGD合成酶（hematopoietic PGD synthase， HPGDS）在中枢神经系统的小胶质细胞中表达，参与PGD_2的生成。（Mohri et al.2003）。抽搐小鼠（GALC^<twi/twi>）是由半乳糖神经酰胺酶缺乏引起的人类球状细胞白质营养不良（Krabbe病）的真实动物模型。在该模型中，脱髓鞘是由出生后30天（PND）后少突胶质细胞（OLs）凋亡引起的，并且总是伴随着小胶质细胞的激活和整个大脑的胶质瘤形成。在本研究中，我们发现在GALC^<twi/twi>脑中，激活的小胶质细胞中HPGDS的表达逐渐上调。这种上调伴随着位于HPGDS^+小胶质细胞附近的增生性星形胶质细胞DP_1受体的诱导。通过对神经胶质细胞的原代培养，我们发现被激活的小胶质细胞可以通过HPGDS产生大量的PGD_2，星形胶质细胞可以同时表达DP_1和DP_2受体并被PGD_2激活。此外，通过对HPGDS-或dp_1缺陷GALC^<twi/twi>小鼠和GALC^<twi/twi>小鼠进行HPGDS抑制剂处理，我们发现阻断HPGDS/PGD_2/DP信号通路可抑制胶质细胞形成和少突胶质细胞凋亡。这是神经炎症中pgd_2介导的小胶质细胞/星形胶质细胞相互作用的第一个例子。

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.