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

Prostaglandin (PG) D₂ is well known as a mediator of inflammation. Hematopoietic PGD synthase (HPGDS) is responsible for the production of PGD₂ involved in inflammatory responses. Microglial activation and astrogliosis are commonly observed during neuroinflammation, 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 PGD₂ receptor, DP₁ and DP₂, and showed enhanced GFAP production after stimulation of either receptor with its respective agonist. These results suggest that PGD₂ plays an important role in microglia/astrocyte interaction. We demonstrated that the blockade of the HPGDS/PGD₂/DP signaling pathway using HPGDS- or DP₂-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.