Dual roles of PGE(2)-EP4 signaling in mouse experimental autoimmune encephalomyelitis

Yoshiyasu Esaki, Youxian Li, Daiji Sakata, Chengcan Yao, Eri Segi-Nishida, Toshiyuki Matsuoka, Kazuhiko Fukuda, Shuh Narumiya*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS). Although prostaglandin (PG) concentrations are increased in cerebrospinal fluid of MS patients, the role of PGs in MS is unknown. We examined this issue by subjecting mice deficient in each PG receptor type or subtype to EAE induction and using agonists or antagonists selective for each of the four PGE receptor (EP) subtypes. Among PG receptor-deficient mice, only EP4(-/-) mice manifested significant suppression of EAE, which was mimicked in wild-type mice and to a greater extent, in EP2(-/-) mice by administration of the EP4 antagonist ONO-AE3-208 during the immunization phase. EP4 antagonism during immunization also suppressed the generation of antigen-specific T helper (Th) 1 and Th17 cells in wild-type mice and to a greater extent, in EP2(-/-) mice. ONO-AE-3208 administration at EAE onset had little effect on disease severity, and its administration throughout the experimental period did not cause significant reduction of the peak of disease, suggesting that, in addition to its facilitative action during the immunization phase, EP4 exerts a preventive action in the elicitation phase. Administration of the EP4 agonist ONO-AE1-329 at EAE onset delayed and suppressed disease progression as well as inhibited the associated increase in permeability of the blood-brain barrier. Thus, PGE(2) exerts dual functions in EAE, facilitating Th1 and Th17 cell generation redundantly through EP4 and EP2 during immunization and attenuating invasion of these cells into the brain by protecting the blood -brain barrier through EP4.

Original languageEnglish
Pages (from-to)12233-12238
Number of pages6
JournalProceedings of the National Academy of Sciences
Volume107
Issue number27
DOIs
Publication statusPublished - 6 Jul 2010

Keywords

  • CEREBROSPINAL-FLUID
  • LEWIS RATS
  • MICE
  • multiple sclerosis
  • CELLS
  • CENTRAL-NERVOUS-SYSTEM
  • PROSTANOID RECEPTORS
  • TH17
  • EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS
  • knockout mice
  • prostaglandin
  • MULTIPLE-SCLEROSIS
  • DISEASE
  • disease model
  • prostaglandin receptor

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