Targeted lipidomics reveals mPGES-1-PGE2 as a therapeutic target for multiple sclerosis.
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 PGD(2)) are produced constitutively in the spinal cord of naive mice. However, in EAE lesions, the PGE(2) pathway is favored and the PGD(2), PGI(2), and 5-lipoxygenase pathways are attenuated. Furthermore, mPGES-1(-/-) mice showed less severe symptoms of EAE and lower production of IL-17 and IFN-gamma than mPGES-1(+/+) mice. Expression of PGE(2) 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-PGE(2)-EPs axis of the AA cascade may exacerbate EAE pathology. Our findings have important implications for the design of therapies for MS.
Kihara
Yasuyuki
Y
Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Matsushita
Takuya
T
Kita
Yoshihiro
Y
Uematsu
Satoshi
S
Akira
Shizuo
S
Kira
Jun-ichi
J
Ishii
Satoshi
S
Shimizu
Takao
T
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D015232:Dinoprostone / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D007150:Immunohistochemistry; D019746:Intramolecular Oxidoreductases / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D008055:Lipids; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000378:metabolism; D000071876:Prostaglandin-E Synthases
D016207:Cytokines; D008055:Lipids; D016718:Arachidonic Acid; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone