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

Yasuyuki Kihara, Takuya Matsushita, Yoshihiro Kita, Satoshi Uematsu, Shizuo Akira, Jun Ichi Kira, Satoshi Ishii, Takao Shimizu

Research output: Contribution to journalArticlepeer-review

93 Citations (Scopus)

Abstract

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 anAAcascade-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.

Original languageEnglish
Pages (from-to)21807-21812
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number51
DOIs
Publication statusPublished - Dec 22 2009

All Science Journal Classification (ASJC) codes

  • General

Fingerprint Dive into the research topics of 'Targeted lipidomics reveals mPGES-1-PGE2 as a therapeutic target for multiple sclerosis'. Together they form a unique fingerprint.

Cite this