Multiple sclerosis is characterized by chronic neuroinflammation and impaired remyelination, highlighting the need for therapies that simultaneously modulate immune responses and promote myelin repair (Franklin & Simons, 2022). Our group recently provided the first evidence that the non-CpG immunomodulatory oligodeoxynucleotide IMT504 promotes remyelination in vivo (Mathieu et al., 2024), although the underlying cellular mechanisms remained unknown. We demostrated that IMT504 was internalized by microglia and oligodendroglial lineage cells. In microglia, IMT504 promoted activation, proliferation and phagocytic activity, induced a balanced inflammatory program characterized by increased IL-1β, TNFα, IFNβ and IL-10 expression, reduced IFNγ levels, and activated ERK1/2, p38, JNK and NF-κB signaling. In oligodendrocyte precursor cells, IMT504 reduced proliferation while accelerating differentiation into morphologically complex mature oligodendrocytes through MAPK activation. Together, these findings identify IMT504 as the first non-CpG oligodeoxynucleotide shown to directly coordinate microglial immunomodulation and oligodendroglial differentiation, providing a strong mechanistic rationale for its application as a remyelination-promoting therapy for multiple sclerosis and other demyelinating disorders.
