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Updated: Jun 12, 2026
Induction of Experimental Autoimmune Encephalomyelitis in Mice and Evaluation of the Disease-dependent Distribution of Immune Cells in Various Tissues
Published on: May 8, 2016
Dual roles of PGE2-EP4 signaling in mouse experimental autoimmune encephalomyelitis
Yoshiyasu Esaki1, Youxian Li, Daiji Sakata
1Departments of Pharmacology and Anesthesiology, Faculty of Medicine, Kyoto University, Kyoto 606-8501, Japan.
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-AE3-208 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.
Insights
Prostaglandin E2 (PGE2) plays a dual role in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS). It promotes T helper cell generation via EP4 and EP2 receptors, while also protecting the blood-brain barrier through EP4.
Area of Science:
- Neuroimmunology
- Inflammation Research
- Prostanoid Signaling
Background:
- Experimental autoimmune encephalomyelitis (EAE) serves as a key animal model for multiple sclerosis (MS).
- Elevated prostaglandin (PG) levels in cerebrospinal fluid of MS patients suggest a potential role for PGs in disease pathogenesis, though this remains largely unknown.
- Prostaglandin E2 (PGE2) exerts diverse biological effects mediated through its four prostanoid (EP) receptor subtypes.
Purpose of the Study:
- To elucidate the specific roles of PGE2 receptor subtypes in the development and progression of EAE.
- To investigate the therapeutic potential of targeting specific EP receptor subtypes in EAE.
Main Methods:
- Induction of EAE in mice genetically deficient in individual EP receptor subtypes.
- Administration of selective EP receptor agonists and antagonists during different phases of EAE.
- Assessment of disease severity, T helper cell differentiation (Th1 and Th17), and blood-brain barrier permeability.
Main Results:
- Mice lacking the EP4 receptor (EP4(-/-)) exhibited significantly suppressed EAE.
- EP4 antagonism during the immunization phase reduced EAE severity and suppressed the generation of antigen-specific Th1 and Th17 cells.
- EP4 activation at EAE onset delayed disease progression and reduced blood-brain barrier permeability, indicating a protective role.
Conclusions:
- PGE2 plays a dual role in EAE: it facilitates Th1 and Th17 cell generation via EP4 and EP2 receptors during immunization.
- EP4 signaling also protects the blood-brain barrier, attenuating immune cell infiltration into the central nervous system during the elicitation phase.
- Targeting EP4 may offer a therapeutic strategy for MS by modulating both immune cell responses and neuroinflammation.
