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Review
. 2016 Sep 15:9:84.
doi: 10.3389/fnmol.2016.00084. eCollection 2016.

NF-κB Pathways in the Pathogenesis of Multiple Sclerosis and the Therapeutic Implications

Saskia M Leibowitz  1 , Jun Yan  1
Affiliations
Review

NF-κB Pathways in the Pathogenesis of Multiple Sclerosis and the Therapeutic Implications

Saskia M Leibowitz et al. Front Mol Neurosci. .

Abstract

Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathways are involved in cell immune responses, apoptosis and infections. In multiple sclerosis (MS), NF-κB pathways are changed, leading to increased levels of NF-κB activation in cells. This may indicate a key role for NF-κB in MS pathogenesis. NF-κB signaling is complex, with many elements involved in its activation and regulation. Interestingly, current MS treatments are found to be directly or indirectly linked to NF-κB pathways and act to adjust the innate and adaptive immune system in patients. In this review, we will first focus on the intricacies of NF-κB signaling, including the activating pathways and regulatory elements. Next, we will theorize about the role of NF-κB in MS pathogenesis, based on current research findings, and discuss some of the associated therapeutic implications. Lastly, we will review four new MS treatments which interrupt NF-κB pathways-fingolimod, teriflunomide, dimethyl fumarate (DMF) and laquinimod (LAQ)-and explain their mechanisms, and the possible strategy for MS treatments in the future.

Keywords: IKK; IκB-α; NF-κB; multiple sclerosis; signaling pathway.

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Figures

Figure 1
Figure 1
The TNF-α-activated canonical nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway. TNF-α triggers TNF-R1 receptor trimerization. TNF receptor type 1-associated death domain protein (TRADD) is then recruited which, in turn, recruits TNF receptor-associated factor 2 (TRAF2) and receptor-interacting protein 1 (RIP1). TRAF2 mediates K63-linked polyubiquitination of RIP1 which allows recruitment of TAB2 and NF-κB essential modulator (NEMO). Following this, TAB2 recruits transforming growth factor beta-activated kinase 1 (TAK1) while NEMO and TRAF2 recruit the IKK complex. TAK1 phosphorylates IKKβ which then phosphorylates IκB-α. IκB-α is then ubiquitinated and degraded, releasing NF-κB and allowing translocation into the nucleus. P, phosphate; U, ubiquitin.
Figure 2
Figure 2
The IL-1β-activated canonical NF-κB signaling pathway. The receptor is activated by IL-1β and recruits MyD88 through homophilic interactions between toll/interleukin-1 receptor (TIR) domains. MyD88 interacts with IRAK1, IRAK2, IRAKM and IRAK4. IRAK4 is phosphorylated and then phosphorylates and activates IRAK1. IRAK1 and IRAK4 interact with TRAF6 which self-ubiquitinates and also ubiquitinates NEMO through Ubc13-Uev1a, in complex with TRAF6. NEMO and TRAF6 recruit TAK1 in complex with TABs1–3. TAK1, activates IKKβ, which then phosphorylates IκB-α. IκB-α is then ubiquitinated and degraded, releasing NF-κB and allowing translocation into the nucleus. P, phosphate; U, ubiquitin.
Figure 3
Figure 3
The LPS-activated canonical NF-κB signaling pathways. (A) TIR-domain-containing adapter-inducing interferon-β (TRIF) is recruited to the TLR4 receptor. TRAF6 and RIP1 are then recruited. TRAF6 is polyubiquitinated and together with RIP1, the two proteins activate TAK1. (B) The MyD88 pathway as described previously for IL-1β. P, phosphate; U, ubiquitin.
Figure 4
Figure 4
Canonical activation of p50. Once activated by normal canonical signaling, IKKβ phosphorylates NF-κB subunit p105, which is the precursor of NF-κB subunit p50. Phosphorylation of p105 generates binding sites for ubiquitin ligases that then target p105 for degradation. p105 also inhibits tumor progression locus 2 (TPL2) by binding with it. Once p105 is degraded, TPL2 is released and stabilized by binding to MEK and ABIN-2. TPL2 then phosphorylates MEK which phosphorylates ERK, ERK1/2 leads to increased TNF-α production and can activate IKK. P, phosphate; U, ubiquitin.
Figure 5
Figure 5
Non-canonical NF-κB signaling pathway. (A) On ligand binding, receptors crosslink and the TRAF2:TRAF3:CIAP1/2 complex is recruited to the receptors. TRAF2 ubiquitinates cIAP1 and cIAP2, which then ubiquitinate TRAF3 (and TRAF2 to some extent) and stimulate its rapid degradation. NF-κB-inducing kinase (NIK) is released. TPL2 physically assembles with IKK and NIK and phosphorylates NIK which then phosphorylates and activates IKKα. TPL2 also activates IKKα. IKKα phosphorylates p100. Once phosphorylated, p100 is degraded by the proteasome and p52 is released and can dimerize and translocate to the nucleus. (B) Dimerization of TRAF3 with TRAF2 allows recruitment of the CIAPs1/2 ubiquitin ligases, Normally, NIK is bound by this complex and targeted for constant ubiquitination and proteasomal degradation. P, phosphate; U, ubiquitin.
Figure 6
Figure 6
Sphingosine signaling. (A) During canonical signaling, when TRAF2 binds to the TNF-α receptor, it recruits SPHK1. SPHK1 catalyzes S1P formation. S1P then acts as a cofactor for TRAF2-mediated K63-linked polyubiquitination of RIP1. (B) S1P also activates ERK1/2 and these together further activate SPHK1. ERK1/2 activation leads to activation of IKK and increased TNF-α production, increasing total flow through the canonical pathway. P, phosphate; U, ubiquitin.
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