Microsomal prostaglandin E synthase-1 aggravates inflammation and demyelination in a mouse model of multiple sclerosis |
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Authors: | Chisen Takeuchi Yoh Matsumoto Kuniko Kohyama Satoshi Uematsu Shizuo Akira Kanato Yamagata Takako Takemiya |
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Affiliation: | 1. Medical Research Institute, Tokyo Women’s Medical University, Tokyo, Japan;2. Kita Medical and Rehabilitation Center for Disabled, Tokyo, Japan;3. Department of Immunotherapy Development, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan;4. Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan;5. Neural Plasticity Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan |
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Abstract: | 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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Keywords: | Prostaglandin E2 (PGE2) Microsomal prostaglandin synthetase-1 (mPGES-1)-deficient mice Experimental allergic encephalomyelitis (EAE) Endothelial cell Inflammation and demyelination Multiple sclerosis (MS) |
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