Hydroxycarboxylic acid receptor 2 mediates dimethyl fumarate's protective effect in EAE.

Area of Science:

• Neuroscience
• Immunology
• Pharmacology

Background:

• Dimethyl fumarate (DMF) is an oral drug improving functional outcomes in multiple sclerosis (MS) patients.
• The precise mechanism of DMF's protective effect in MS remains incompletely understood.
• DMF and its metabolite monomethyl fumarate are agonists of hydroxycarboxylic acid receptor 2 (HCA₂).

Purpose of the Study:

• To investigate the role of HCA₂ in mediating the therapeutic effects of DMF.
• To determine if HCA₂ is essential for DMF's protective actions in a mouse model of MS.

Main Methods:

• Utilized the experimental autoimmune encephalomyelitis (EAE) mouse model, a standard model for MS.
• Administered DMF to wild-type and HCA₂-deficient (Hca2⁻/⁻) mice.
• Assessed neurological deficits, spinal cord immune cell infiltration, and demyelination.

Main Results:

• DMF treatment significantly reduced neurological deficits, immune cell infiltration, and demyelination in wild-type mice.
• These protective effects were absent in Hca2⁻/⁻ mice, demonstrating HCA₂ dependency.
• DMF specifically decreased neutrophil infiltration in a HCA₂-dependent manner, potentially by inhibiting neutrophil adhesion and chemotaxis.

Conclusions:

• Hydroxycarboxylic acid receptor 2 (HCA₂) is essential for mediating the therapeutic effects of dimethyl fumarate (DMF) in the EAE model.
• HCA₂ activation is a key mechanism underlying DMF's neuroprotective and immunomodulatory actions.
• Targeting HCA₂ may offer a strategy for optimizing future MS therapies.