Prostaglandin D2-Mediated Microglia/Astrocyte Interaction Enhances Astrogliosis and Demyelination in twitcher

Abstract

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 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 DP 1 receptor for PGD 2 in the brain of these mice. Cultured microglia actively produced PGD 2 by the action of HPGDS. Cultured astrocytes expressed two types of PGD 2 receptor, DP 1 and DP 2, 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 DP 1-null twitcher mice, and twitcher mice treated with an HPGDS inhibitor, HQL-79 (4-benzhydryloxy-1-[3-(1 H-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 PGD 2 is the key neuroinflammatory molecule that heightens the pathological response to demyelination in twitcher mice.