Microsomal prostaglandin E synthase-1 aggravates inflammation and demyelination in a mouse model of multiple sclerosis

Microsomal prostaglandin synthetase-1 (mPGES-1) is an inducible terminal enzyme required for prostaglandin E2 (PGE2) biosynthesis. In this study, we examined the role of mPGES-1 in the inflammation and demyelination observed in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). We induced EAE with myelin oligodendrocyte glycoprotein35–55 peptide in mPGES-1-deficient (mPGES-1−/−) and wild-type (WT) mice. First, we examined the histopathology in the early and late phases of EAE progression. Next, we measured the concentration of PGE2 in the spinal cord and investigated the expression of mPGES-1 using immunohistochemistry. In addition, we examined the progression of the severity of EAE using an EAE score to investigate a correlation between pathological features and paralysis. In this paper, we demonstrate that WT mice showed extensive inflammation and demyelination, whereas mPGES-1−/− mice exhibited significantly smaller and more localized changes in the perivascular area. The mPGES-1 protein was induced in vascular endothelial cells and microglia around inflammatory foci, and PGE2 production was increased in WT mice but not mPGES-1−/− mice. Furthermore, mPGES-1−/− mice showed a significant reduction in the maximum EAE score and improved locomotor activity. These results suggest that central PGE2 derived from non-neuronal mPGES-1 aggravates the disruption of the vessel structure, leading to the spread of inflammation and local demyelination in the spinal cord, which corresponds to the symptoms of EAE. The inhibition of mPGES-1 may be useful for the treatment of human MS.

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► PGE2 is increased in WT EAE mice, an animal model of multiple sclerosis.
► mPGES-1 is induced in vascular endothelium and microglia in WT EAE mice.
► mPGES-1−/− mice exhibited more localized inflammation in the perivascular area.
► mPGES-1−/− mice exhibited more localized demyelination in the perivascular area.
► Both WT and mPGES-1−/− EAE showed Th1Th17 cells in inflammatory lesion.