Enhanced glycolytic metabolism supports transmigration of brain-infiltrating macrophages in multiple sclerosis

Area of Science:

• Neuroimmunology
• Cellular Metabolism
• Neuroinflammation

Background:

• Leukocyte migration into the central nervous system (CNS) is a key driver of multiple sclerosis (MS) neuropathology.
• The specific energy pathways supporting this leukocyte transmigration remain incompletely understood.

Purpose of the Study:

• To investigate the metabolic processes, specifically glycolysis, employed by macrophages during CNS infiltration in the experimental autoimmune encephalomyelitis (EAE) model of MS.
• To identify key molecular players involved in macrophage metabolism and transmigration and assess their therapeutic potential.

Main Methods:

• Utilized the EAE mouse model of MS.
• Assessed macrophage glycolysis via lactate dehydrogenase A (LDHA) and monocarboxylate transporter-4 (MCT-4) expression.
• Performed siRNA-mediated knockdown of LDHA, MCT-4, and EMMPRIN (CD147).
• Investigated MCT-4/EMMPRIN interactions using co-expression and co-immunoprecipitation.
• Tested the efficacy of the MCT-4 inhibitor α-cyano-4-hydroxy-cinnamic acid (CHCA) in vitro and in vivo.

Main Results:

• Macrophages in EAE exhibited high glycolytic activity, evidenced by strong LDHA and MCT-4 expression.
• Knockdown of LDHA and MCT-4 reduced lactate secretion and macrophage transmigration.
• EMMPRIN regulates MCT-4, and its inhibition decreased macrophage transmigration.
• CHCA treatment reduced macrophage transmigration, leukocyte infiltration, and EAE clinical severity.
• Elevated MCT-4, EMMPRIN, and LDHA expression was observed in perivascular macrophages in MS patient brains.

Conclusions:

• Macrophage transmigration into the CNS in MS is dependent on glycolysis and lactate secretion, mediated by MCT-4 and regulated by EMMPRIN.
• Inhibition of this metabolic pathway, for example, with CHCA, presents a potential therapeutic strategy for MS.
• Dietary modifications targeting these metabolic pathways may offer novel approaches for managing neuroinflammation in MS.