NF-κB signaling regulates myelination in the CNS

Abstract

Besides myelination of neuronal axons by oligodendrocytes to facilitate propagation of action potentials, oligodendrocytes also support axon survival and function. A key transcription factor involved in these processes is nuclear factor-κB (NF-κB), a hetero or homodimer of the Rel family of proteins, including p65, c-Rel, RelB, p50, and p52. Under unstimulated, NF-κB remains inactive in the cytoplasm through interaction with NF-κB inhibitors (IκBs). Upon activation of NF-κB the cytoplasmic IκBs gets degradated, allowing the translocation of NF-κB into the nucleus where the dimer binds to the κB consensus DNA sequence and regulates gene transcription. In this review we describe how oligodendrocytes are, directly or indirectly via neighboring cells, regulated by NF-κB signaling with consequences for innate and adaptive immunity and for regulation of cell apoptosis and survival.

Keywords: NF-κB pathway; demyelination; myelin; oligodendrocyte; oligodendrocyte precursor cells; remyelination.

FIGURE 1

Signals in the regulation of myelination, de- and remyelination in the CNS with a focus on NF-κB. Myelination involves a sequence of orchestrated steps, where PSA-NCAM is downregulated in neurons and astrocytes, and neurons release several growth/trophic factors such as NRG-1 and regulate oligodendrocyte survival and maturation by upregulating SHP1. Oligodendrocytes provide trophic support to axons and promote their viability via upregulation of MCT1 and the release of lactate. There is no activation of NF-κB in astrocytes or oligodendrocytes (1). When myelinated axons undergo demyelination, myelin debris is phagocytized by microglia. Resident astrocytes and microglia get activated and produce glutamate in addition to inflammatory signals such as IL6, NO, ADAM12, and TNFα. Activated astrocytes and microglia show elevated NF-κB activation and produce factors that activate each other. The role of NF-κB in neurons is unclear at present. NF-κB in oligodendrocytes is not activated (2). Under the influence of yet unknown factors that are produced by non-activated microglia and potentially by non-activated astrocytes, NF-κB is activated in recruited oligodendrocyte progenitor cells that engage demyelinated axons and differentiate into remyelinating oligodendrocytes (3). Color code on the left represents cell type.