Prostaglandin D<sub>2</sub>-Mediated Microglia/Astrocyte Interaction Enhances Astrogliosis and Demyelination in<i>twitcher</i>

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書誌事項

公開日
2006-04-19
権利情報
  • https://creativecommons.org/licenses/by-nc-sa/4.0/
DOI
  • 10.1523/jneurosci.4531-05.2006
  • 10.17615/sj66-aj08
公開者
Society for Neuroscience

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説明

<jats:p>Prostaglandin (PG) D<jats:sub>2</jats:sub>is well known as a mediator of inflammation. Hematopoietic PGD synthase (HPGDS) is responsible for the production of PGD<jats:sub>2</jats:sub>involved in inflammatory responses. Microglial activation and astrogliosis are commonly observed during neuroinflammation, including that which occurs during demyelination. Using the genetic demyelination mouse<jats:italic>twitcher</jats:italic>, a model of human Krabbe’s disease, we discovered that activated microglia expressed HPGDS and activated astrocytes expressed the DP<jats:sub>1</jats:sub>receptor for PGD<jats:sub>2</jats:sub>in the brain of these mice. Cultured microglia actively produced PGD<jats:sub>2</jats:sub>by the action of HPGDS. Cultured astrocytes expressed two types of PGD<jats:sub>2</jats:sub>receptor, DP<jats:sub>1</jats:sub>and DP<jats:sub>2</jats:sub>, and showed enhanced GFAP production after stimulation of either receptor with its respective agonist. These results suggest that PGD<jats:sub>2</jats:sub>plays an important role in microglia/astrocyte interaction. We demonstrated that the blockade of the HPGDS/PGD<jats:sub>2</jats:sub>/DP signaling pathway using HPGDS- or DP<jats:sub>1</jats:sub>-null<jats:italic>twitcher</jats:italic>mice, and<jats:italic>twitcher</jats:italic>mice treated with an HPGDS inhibitor, HQL-79 (4-benzhydryloxy-1-[3-(1<jats:italic>H</jats:italic>-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<jats:italic>twitcher</jats:italic>mice. These results suggest that PGD<jats:sub>2</jats:sub>is the key neuroinflammatory molecule that heightens the pathological response to demyelination in<jats:italic>twitcher</jats:italic>mice.</jats:p>

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