Remodeling oligodendrocyte lipid metabolism via liver X receptors overcomes inflammatory blockade of remyelination

Multiple sclerosis is a disease marked by immune-mediated damage to the protective myelin sheath coating nerve fibers. This impairs the ability of oligodendrocyte precursor cells (OPCs) to differentiate into mature myelinating oligodendrocytes (OLs). Inflammatory cytokines present in MS lesions interfere with OPC maturation, transforming them into antigen-presenting cells with immune-like characteristics. However, the specific mechanisms behind this inflammation-induced remyelination failure are unclear.

The study found that inflammation alters OPC lipid metabolism, switching from lipid synthesis to utilization. This shift results in lower intracellular fatty acid levels and increased reliance on fatty acid oxidation. In cultured rodent OPCs, interferon-gamma (IFN-gamma) treatment induced this metabolic reprogramming. Transcriptomic analysis revealed comparable lipid metabolic changes in OL-lineage cells derived from human surgical specimens or mouse models of inflammatory demyelination and human multiple sclerosis lesions.

Boosting fatty acid availability in OPCs either by supplying oleic acid or blocking fatty acid oxidation helped relieve immune-like functions and improve differentiation. Moreover, activating transcription factors known as liver X receptors (LXR) modified lipid metabolism, reduced immune-like properties, and overcame IFN-gamma-induced differentiation blockage in both mouse and human OPCs.

In a mouse model where inflammation hinders remyelination, LXR activation boosted the production of mature OLs and accelerated myelin repair.

These findings suggest that inflammation can reprogram OPC lipid metabolism, contributing to remyelination failure. Activation of LXR offers a potential therapeutic avenue to enhance remyelination in multiple sclerosis by rebalancing lipid metabolism and suppressing immune-like functions in OPCs.