Role of nuclear factor kappa B in central nervous system regeneration

Abstract

Activation of nuclear factor kappa B (NF-κB) is a hallmark of various central nervous system (CNS) pathologies. Neuron-specific inhibition of its transcriptional activator subunit RelA, also referred to as p65, promotes neuronal survival under a range of conditions, i.e., for ischemic or excitotoxic insults. In macro- and microglial cells, post-lesional activation of NF-κB triggers a growth-permissive program which contributes to neural tissue inflammation, scar formation, and the expression of axonal growth inhibitors. Intriguingly, inhibition of such inducible NF-κB in the neuro-glial compartment, i.e., by genetic ablation of RelA or overexpression of a transdominant negative mutant of its upstream regulator IκBα, significantly enhances functional recovery and promotes axonal regeneration in the mature CNS. By contrast, depletion of the NF-κB subunit p50, which lacks transcriptional activator function and acts as a transcriptional repressor on its own, causes precocious neuronal loss and exacerbates axonal degeneration in the lesioned brain. Collectively, the data imply that NF-κB orchestrates a multicellular program in which κB-dependent gene expression establishes a growth-repulsive terrain within the post-lesioned brain that limits structural regeneration of neuronal circuits. Considering these subunit-specific functions, interference with the NF-κB pathway might hold clinical potentials to improve functional restoration following traumatic CNS injury.

Keywords: RelA; axonal regeneration; central nervous system injury; neural regeneration; nuclear factor kappa B; p50; p65.

Figure 1

Schematic representation of nuclear factor kappaB (NF-êB) subunit and cell type-specific activation patterns in traumatic nerve injury. In naïve neurons, p50 is required for survival and axonal maintenance. Nerve injury induces activation of RelA in associated neuronal soma, thereby promoting apoptosis. Shifting the balance between RelA and p50 towards p50, e.g., by conditional deletion of RelA promotes neuronal survival. During the primary phase of injury, RelA likewise becomes activated in myeloid cells/activated microglia and astrocytes at the lesion site. RelA-dependent secretion of pro-inflammatory cytokines and chemokines (red dots) exacerbates neuronal damage. During wound healing and glial scar formation, activation of RelA in astrocytes and oligodendrocytes contributes to the (re-)expression of membrane-associated growth inhibitors (black symbols), thus leading to permanent growth-repulsion of regenerating axons.