Tumor necrosis factor (TNF) is associated with the pathophysiology of various
neurological disorders, including
multiple sclerosis. It exists as a transmembrane form tmTNF, signaling via
TNF receptor 2 (
TNFR2) and
TNFR1, and a soluble form, solTNF, signaling via
TNFR1.
Multiple sclerosis is associated with the detrimental effects of solTNF acting through
TNFR1, while tmTNF promotes repair and remyelination. Here we demonstrate that oligodendroglial
TNFR2 is a key mediator of tmTNF-dependent protection in
experimental autoimmune encephalomyelitis (EAE). CNP-cre:
TNFR2(fl/fl) mice with
TNFR2 ablation in oligodendrocytes show exacerbation of the disease with increased axon and myelin pathology, reduced remyelination, and increased loss of oligodendrocyte precursor cells and mature oligodendrocytes. The
clinical course of EAE is not improved by the solTNF inhibitor
XPro1595 in CNP-cre:
TNFR2(fl/fl) mice, indicating that for tmTNF to promote recovery
TNFR2 in oligodendrocytes is required. We show that
TNFR2 drives differentiation of oligodendrocyte precursor cells, but not proliferation or survival.
TNFR2 ablation leads to dysregulated expression of
microRNAs, among which are regulators of oligodendrocyte differentiation and
inflammation, including miR-7a. Our data provide the first direct in vivo evidence that
TNFR2 in oligodendrocytes is important for oligodendrocyte differentiation, thereby sustaining tmTNF-dependent repair in neuroimmune disease. Our studies identify
TNFR2 in the CNS as a molecular target for the development of remyelinating agents, addressing the most pressing need in
multiple sclerosis therapy nowadays.
SIGNIFICANCE STATEMENT: Our study, using novel
TNF receptor 2 (
TNFR2) conditional KO mice with selective
TNFR2 ablation in oligodendrocytes, provides the first direct evidence that
TNFR2 is an important signal for oligodendrocyte differentiation. Following activation by transmembrane TNF,
TNFR2 initiates pathways that drive oligodendrocytes into a reparative mode contributing to remyelination following disease. This identifies
TNFR2 as a new molecular target for the development of therapeutic agents in
multiple sclerosis.