PT  - JOURNAL ARTICLE
AU  - Ikuko Mohri
AU  - Masako Taniike
AU  - Hidetoshi Taniguchi
AU  - Takahisa Kanekiyo
AU  - Kosuke Aritake
AU  - Takashi Inui
AU  - Noriko Fukumoto
AU  - Naomi Eguchi
AU  - Atsuko Kushi
AU  - Hitoshi Sasai
AU  - Yoshihide Kanaoka
AU  - Keiichi Ozono
AU  - Shuh Narumiya
AU  - Kinuko Suzuki
AU  - Yoshihiro Urade
TI  - Prostaglandin D<sub>2</sub>-Mediated Microglia/Astrocyte Interaction Enhances Astrogliosis and Demyelination in <em>twitcher</em>
AID  - 10.1523/JNEUROSCI.4531-05.2006
DP  - 2006 Apr 19
TA  - The Journal of Neuroscience
PG  - 4383--4393
VI  - 26
IP  - 16
4099  - http://www.jneurosci.org/content/26/16/4383.short
4100  - http://www.jneurosci.org/content/26/16/4383.full
SO  - J. Neurosci.2006 Apr 19; 26
AB  - 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 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.