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的生物学作用是通过与DP_1或DP_2受体结合来实现的。造血PGD合成酶(HPGDS)负责PGD_2的产生，表达于中枢神经系统的小胶质细胞。(Mohri等人，2003年)。抽动小鼠(GALC^&lt；twi/twi&gt；)是由半乳糖基神经酰胺酶缺乏引起的人类脑白质营养不良(Krabbe病)的真实动物模型。在这种模型中，脱髓鞘是由出生后30天(PND)后少突胶质细胞(OLs)的凋亡引起的，并总是伴随着小胶质细胞的激活和整个脑内的胶质细胞增生。在这项研究中，我们发现在GALC^&lt；Ti/Ti&gt；脑内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^+小胶质细胞附近的肥大星形胶质细胞中DP_1受体的诱导。通过对胶质细胞的原代培养，我们发现激活的小胶质细胞通过HPGDS产生大量的PGD_2，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&GT；小鼠和HPGDS抑制剂处理的GALC^/TWI&GT；小鼠，我们发现阻断HPGDS/PGD_2/DP信号通路导致胶质增生和少突胶质细胞凋亡的抑制。这是第一例PGD_2介导的小胶质细胞/星形胶质细胞在神经炎症中的相互作用。

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.