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The Journal of Neuroscience, April 19, 2006, 26(16):4383-4393; doi:10.1523/JNEUROSCI.4531-05.2006

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

Ikuko Mohri,^1,2,3 * Masako Taniike,^1 * Hidetoshi Taniguchi,¹ Takahisa Kanekiyo,¹ Kosuke Aritake,² Takashi Inui,² Noriko Fukumoto,² Naomi Eguchi,² Atsuko Kushi,⁴ Hitoshi Sasai,⁴ Yoshihide Kanaoka,^2,5 Keiichi Ozono,¹ Shuh Narumiya,⁶ Kinuko Suzuki,³ and Yoshihiro Urade²

¹Department of Developmental Medicine (Pediatrics), Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan, ²Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Suita, Osaka 565-0874, Japan, ³Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27514, ⁴Japan Tobacco, Pharmaceutical Frontier Research Laboratories, Kanazawa-ku, Yokohama 236-0004, Japan, ⁵Department of Medicine, Harvard Medical School, and Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Boston, Massachusetts 02115, and ⁶Department of Pharmacology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan

Correspondence should be addressed to either of the following: Yoshihiro Urade, Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Suita, Osaka 565-0874, Japan, Email: uradey{at}obi.or.jp or Masako Taniike, Department of Developmental Medicine (Pediatrics), Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan, masako{at}ped.med.osaka-u.ac.jp

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.

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Received June 7, 2005; revised March 2, 2006; accepted March 12, 2006.

Correspondence should be addressed to either of the following: Yoshihiro Urade, Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Suita, Osaka 565-0874, Japan, Email: uradey{at}obi.or.jp or Masako Taniike, Department of Developmental Medicine (Pediatrics), Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan, masako{at}ped.med.osaka-u.ac.jp

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