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Published on: June 29, 2015
Prostaglandin D2-mediated microglia/astrocyte interaction enhances astrogliosis and demyelination in twitcher
Ikuko Mohri1, Masako Taniike, Hidetoshi Taniguchi
1Department of Developmental Medicine (Pediatrics), Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
Abstract:
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.
Insights
Prostaglandin D2 (PGD2) drives neuroinflammation and demyelination in Krabbe
Area of Science:
- Neuroimmunology
- Neuroinflammation
- Demyelinating Diseases
Background:
- Prostaglandin D2 (PGD2) is a known mediator of inflammation.
- Microglial activation and astrogliosis are hallmarks of neuroinflammation, particularly in demyelinating conditions.
- The twitcher mouse model mimics human Krabbe's disease, a severe demyelinating disorder.
Purpose of the Study:
- To investigate the role of PGD2 in microglia-astrocyte interactions during neuroinflammation in the twitcher mouse model.
- To determine if targeting the PGD2 pathway can ameliorate pathological features of demyelination.
Main Methods:
- Analysis of HPGDS and DP receptor expression in microglia and astrocytes from twitcher mice.
- In vitro studies of PGD2 production by cultured microglia and its effects on astrocytes.
- Pharmacological and genetic blockade of the HPGDS/PGD2/DP signaling pathway in twitcher mice.
- Assessment of neuroinflammation, demyelination, motor function, and oligodendrocyte apoptosis.
Main Results:
- Activated microglia expressed hematopoietic PGD synthase (HPGDS), producing PGD2.
- Activated astrocytes expressed the PGD2 receptor DP1.
- Blocking the HPGDS/PGD2/DP pathway significantly reduced astrogliosis, demyelination, motor deficits, and oligodendrocyte apoptosis in twitcher mice.
Conclusions:
- PGD2 acts as a key neuroinflammatory mediator exacerbating demyelination in the twitcher mouse model.
- Targeting the PGD2 signaling pathway offers a potential therapeutic strategy for demyelinating diseases like Krabbe's disease.
