NF-kappaB Signaling Pathways in Neurological Inflammation: A Mini Review

Abstract

The NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells) transcription factor family is a pleiotropic regulator of many cellular signaling pathways, providing a mechanism for the cells in response to a wide variety of stimuli linking to inflammation. The stimulated cells will be regulated by not only the canonical but also non-canonical NF-κB pathways. To initiate both of these pathways, IκB-degradation triggers NF-κB release and the nuclear translocated-heterodimer (or homodimer) can associate with the κB sites of promoter to regulate the gene transcriptions. NF-κB ubiquitously expresses in neurons and the constitutive NF-κB activation is associated with processing of neuronal information. NF-κB can regulate the transcription of genes such as chemokines, cytokines, proinflammatory enzymes, adhesion molecules, proinflammatory transcription factors, and other factors to modulate the neuronal survival. In neuronal insult, NF-κB constitutively active in neuron cell bodies can protect neurons against different injuries and regulate the neuronal inflammatory reactions. Besides neurons, NF-κB transcription factors are abundant in glial cells and cerebral blood vessels and the diverse functions of NF-κB also regulate the inflammatory reaction around the neuronal environment. NF-κB transcription factors are abundant in the brain and exhibit diverse functions. Several central nerve system (CNS) diseases are linked to NF-κB activated by inflammatory mediators. The RelA and c-Rel expression produce opposite effects on neuronal survival. Importantly, c-Rel expression in CNS plays a critical role in anti-apoptosis and reduces the age-related behaviors. Moreover, the different subunits of NF-κB dimer formation can modulate the neuroninflammation, neuronal protection, or neurotoxicity. The diverse functions of NF-κB depend on the subunits of the NF-κB dimer-formation which enable us to develop a therapeutic approach to neuroinflammation based on a new concept of inflammation as a strategic tool in neuronal cells. However, the detail role of NF-κB in neuroinflammation, remains to be clarified. In the present article, we provide an updated review of the current state of our knowledge about relationship between NF-κB and neuroinflammation.

Keywords: NF-kappaB; adhesion molecules; neuroinflammation; neuroprotection; proinflammatory transcription factors.

FIGURE 1

Schematic representation of the canonical and non-canonical nuclear factor (NF)-κB activation pathways. The canonical NF-κB pathway (upper) can be activated by a wide range of various stimuli, including tumor necrosis factor (TNF)-α, interlukin (IL)-1, lipopolysaccharide (LPS), and Toll-like receptors ligand (such as CD40L). Initiation of the canonical pathway via Toll-like receptor or cytokine receptor signaling depends on the inhibitor of κB kinase (IKK) complex, which is composed of the kinases IKKα and IKKβ, and the regulatory subunit IKKγ (NEMO). Activated IKK phosphorylates the inhibitory subunit IκBα leading to its degradation. The released NF-κB dimers (p50-p65) translocate to the nucleus and bind to κB site of chromosome to induce transcription of NF-κB targeted genes. The non-canonical pathway (lower) is activated by specific stimuli including B cell activating factor (BAF) belonging to the TNF family receptor, LPS, lymphotoxin (LT) α1β2, receptor activator of NF-κB (RANK), and CD40L. NF-κB inducing kinase (NIK) is stabilized. When stimulated, NIK is activated and recruits IKKα to the p100 complex to phosphorylate p100, leading to p100 ubiquitination. P52, the processing product of p100, generates the activated p52/RelB NF-κB complex, which is able to translocate to the nucleus and induce the downstream gene expressions.

FIGURE 2

The role of NF-κB in neurological damage. Chemical/mechanical stimulation (such as glutamate excitotoxicity, bacteria/virus infection, ischemic/hemorrhagic stroke, or oxidative stress) to the brain/spinal cord tissue results in initial injury, including glutamate neuron-excitotoxicity, and cytokine-mediated inflammation which increase oxidative stress linking to neuroinflammatory response. NF-κB transcription factors are abundant in the brain where they have diverse functions between neuron, glia, and cerebral blood vessels. Constitutive NF-κB transduction factors are responsible for neurogenesis, neuritogenesis, synaptic plasticity, learning, and memory. Either glial or endothelial inducible NF-κB activation was implicated in neuroinflammation-associated pathogenesis related to secondary neuronal damage, while p50/RelA and p50/c-Rel subunit within activated NF-κB dimers play different roles on neuronal pathogenesis in neuron. The p50/RelA enhances damage by inducing the expression of the 1B isoform of the divalent metal transporter-1(1B/DMT1), p50/c-Rel protects against the damage by increasing the transcription of gene of Bcl-Xl or MnSOD. NF-κB transcription factors have diverse functions that depend on the composition of the NF-κB complex and cell types.