RT Journal Article
SR Electronic
T1 Prostaglandin D<sub>2</sub>-Mediated Microglia/Astrocyte Interaction Enhances Astrogliosis and Demyelination in <em>twitcher</em>
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 4383
OP 4393
DO 10.1523/JNEUROSCI.4531-05.2006
VO 26
IS 16
A1 Ikuko Mohri
A1 Masako Taniike
A1 Hidetoshi Taniguchi
A1 Takahisa Kanekiyo
A1 Kosuke Aritake
A1 Takashi Inui
A1 Noriko Fukumoto
A1 Naomi Eguchi
A1 Atsuko Kushi
A1 Hitoshi Sasai
A1 Yoshihide Kanaoka
A1 Keiichi Ozono
A1 Shuh Narumiya
A1 Kinuko Suzuki
A1 Yoshihiro Urade
YR 2006
UL http://www.jneurosci.org/content/26/16/4383.abstract
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.