Prostaglandin D₂-Mediated Microglia/Astrocyte Interaction Enhances Astrogliosis and Demyelination intwitcher

Abstract

Prostaglandin (PG) D 2 is well known as a mediator of inflammation. Hematopoietic PGD synthase (HPGDS) is responsible for the production of PGD 2 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 DP 1 receptor for PGD 2 in the brain of these mice. Cultured microglia actively produced PGD 2 by the action of HPGDS. Cultured astrocytes expressed two types of PGD 2 receptor, DP 1 and DP 2 , and showed enhanced GFAP production after stimulation of either receptor with its respective agonist. These results suggest that PGD 2 plays an important role in microglia/astrocyte interaction. We demonstrated that the blockade of the HPGDS/PGD 2 /DP signaling pathway using HPGDS-or DP 1 -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 PGD 2 is the key neuroinflammatory molecule that heightens the pathological response to demyelination in twitcher mice.

Prostaglandin D2Protects Neonatal Mouse Brain from Hypoxic Ischemic Injury

“…We found previously that both L-PGDS (Taniike et al, 2002) and HPGDS (Mohri et al, 2006) were upregulated together with specific elevation of PGD 2 in the brains of twitcher mice, a model of chronic neuroinflammation. Suppression of HPGDS-PGD 2 -DP 1 signaling resulted in the clinicopathological improvement in twitcher (Mohri et al, 2006).…”

“…HPGDS knock-out (H-KO) (Mohri et al, 2006), L-PGDS knock-out (L-KO) (Eguchi et al, 1999), and DP 1 knock-out (DP 1 -KO) (Matsuoka et al, 2000) mice were generated by standard gene targeting technology with embryonic stem cells derived from the 129 strain of mouse. H-KO, L-KO, and DP 1 -KO mice were backcrossed to the inbred C57BL/6J strain 15 times.…”

IFNγ triggers a LIGHT-dependent selective death of motoneurons contributing to the non-cell-autonomous effects of mutant SOD1

“…In particular, it has been suggested that prostaglandin D 2 (PGD 2 ) contributes to astrocyte-derived toxicity. 5 Interestingly, it has been demonstrated that the genetic or pharmacological inhibition of the PGD 2 /PGD 2 receptor signaling markedly reduced astrogliosis, 30 IFNc triggers a motoneuron-selective death pathway J Aebischer et al tion whether PGD 2 function directly on motoneurons as a death trigger and/or indirectly by consolidating the inflammatory phenotype of mutant astrocytes. In the present study, we show that inhibition of IFNg activity by antagonist antibodies greatly improves the survival of motoneurons cocultured with mutant astrocytes, whereas blocking the interaction between LIGHT and LT-bR by LT-bR-Fc produced a more moderate improvement in motoneuron survival.…”

PGD2 deficiency exacerbates food antigen-induced mast cell hyperplasia

“…All experiments were approved by The University of Tokyo's Institutional Animal Care and Use Committee. Five-to eight-week-old female H-PGDS À / À (C57BL/6 and Balb/c) and littermates control mice or CXCR4 flox/flox mice (C57BL/6) were generated and bred as described previously 49,50 . Four-week-old female Kit W-sh/W-sh (C57BL/6) mice were generously provided by RIKEN BioResource Center.…”