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

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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.