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

Prostaglandin (PG) D-2 is well known as a mediator of inflammation. Hematopoietic PGD synthase (HPGDS) is responsible for the production of PGD(2) involved in inflammatory responses. Microglial activation and astrogliosis are commonly observed during neuro-inflammation, 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 PGD(2) receptor, DP1 and DP2, and showed enhanced GFAP production after stimulation of either receptor with its respective agonist. These results suggest that PGD(2) plays an important role in microglia/astrocyte interaction. We demonstrated that the blockade of the HPGDS/PGD(2)/DP signaling pathway using HPGDS- or DP1-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.