Targeted lipidomics reveals mPGES-1-PGE2 as a therapeutic target for multiple sclerosis

• Published in: Proceedings of the National Academy of Sciences - PNAS 2009-12, Vol.106 (51), p.21807-21812
• Main Authors: Kihara, Yasuyuki, Matsushita, Takuya, Kita, Yoshihiro, Uematsu, Satoshi, Akira, Shizuo, Kira, Jun-ichi, Ishii, Satoshi, Shimizu, Takao
• Format: Article
• Language: English
• Subjects: Animals; Arachidonic Acid - metabolism; Biological Sciences; Cytokines; Cytokines - biosynthesis; Dinoprostone - metabolism; Disease Models, Animal; Eicosanoids; Enzymes; Gene expression; Humans; Immunohistochemistry; Inflammation; Intramolecular Oxidoreductases - drug effects; Intramolecular Oxidoreductases - genetics; Intramolecular Oxidoreductases - metabolism; Lesions; Lipids; Mice; Mice, Inbred C57BL; Mice, Knockout; Multiple sclerosis; Multiple Sclerosis - drug therapy; Multiple Sclerosis - metabolism; Nonsteroidal anti-inflammatory drugs; Pathology; Prostaglandin-E Synthases; Prostaglandins; Rodents; Side effects; T lymphocytes
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0906891106

The arachidonic acid (AA) cascade produces eicosanoids, such as prostaglandins (PGs), that regulate physiological and pathological functions. Although various nonsteroidal anti-inflammatory drugs have been developed, blocking upstream components (cyclooxygenase-1 and -2) of the AA cascade leads to severe side effects, including gastrointestinal ulcers and cardiovascular events, respectively, due to the complexity of the AA cascade. Here, using an AA cascade-targeted lipidomics approach, we report that microsomal PGE synthase 1 (mPGES-1) plays a key role in experimental autoimmune encephalomyelitis (EAE). Eicosanoids (mainly PGD₂) are produced constitutively in the spinal cord of naive mice. However, in EAE lesions, the PGE₂ pathway is favored and the PGD₂, PGI₂, and 5-lipoxygenase pathways are attenuated. Furthermore, mPGES-1⁻/⁻ mice showed less severe symptoms of EAE and lower production of IL-17 and IFN-γ than mPGES-1⁺/⁺ mice. Expression of PGE₂ receptors (EP1, EP2, and EP4) was elevated in EAE lesions and correlated with clinical symptoms. Immunohistochemistry on central nervous systems of EAE mice and multiple sclerosis (MS) patients revealed overt expression of mPGES-1 protein in microglia/macrophages. Thus, the mPGES-1-PGE₂-EPs axis of the AA cascade may exacerbate EAE pathology. Our findings have important implications for the design of therapies for MS.