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

Leibowitz, Saskia M.; Yan, Jun

doi:10.3389/fnmol.2016.00084

Cited by 88 publications

(47 citation statements)

References 219 publications

(374 reference statements)

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“…This suggests that treatments that reduce peripheral inflammation or the activation of NF-κB may reduce the deleterious effects of sustained hyperammonemia and hepatic encephalopathy. The use of molecules to inhibit elements of the NF-κB signaling pathway has also been suggested as a therapeutic option for neurological disorders such as [56] multiple sclerosis, Parkinson's disease [57], Alzheimer's disease [58], and spontaneous intracerebral hemorrhage [38].…”

Section: Discussionmentioning

confidence: 99%

Sustained hyperammonemia induces TNF-a IN Purkinje neurons by activating the TNFR1-NF-κB pathway

Balzano

Arenas

Dadsetan

et al. 2020

J Neuroinflammation

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Background: Patients with liver cirrhosis may develop hepatic encephalopathy. Rats with chronic hyperammonemia exhibit neurological alterations mediated by peripheral inflammation and neuroinflammation. Motor incoordination is due to increased TNF-a levels and activation of its receptor TNFR1 in the cerebellum. The aims were to assess (a) whether peripheral inflammation is responsible for TNF-a induction in hyperammonemic rats, (b) the cell type(s) in which TNF-a is increased, (c) whether this increase is associated with increased nuclear NF-κB and TNFR1 activation, (d) the time course of TNF-a induction, and (e) if TNF-a is induced in the Purkinje neurons of patients who die with liver cirrhosis. Methods:We analyzed the level of TNF-a mRNA and NF-κB in microglia, astrocytes, and Purkinje neurons in the cerebellum after 1, 2, and 4 weeks of hyperammonemia. We assessed whether preventing peripheral inflammation by administering an anti-TNF-a antibody prevents TNF-a induction. We tested whether TNF-a induction is reversed by R7050, which inhibits the TNFR1-NF-κB pathway, in ex vivo cerebellar slices. Results: Hyperammonemia induced microglial and astrocyte activation at 1 week. This was followed by TNF-a induction in both glial cell types at 2 weeks and in Purkinje neurons at 4 weeks. The level of TNF-a mRNA increased in parallel with the TNF-a protein level, indicating that TNF-a was synthesized in Purkinje cells. This increase was associated with increased NF-κB nuclear translocation. The nuclear translocation of NF-κB and the increase in TNF-a were reversed by R7050, indicating that they were mediated by the activation of TNFR1. Preventing peripheral inflammation with an anti-TNF-a antibody prevents TNF-a induction. Conclusion: Sustained (4 weeks) but not short-term hyperammonemia induces TNF-a in Purkinje neurons in rats. This is mediated by peripheral inflammation. TNF-a is also increased in the Purkinje neurons of patients who die with liver cirrhosis. The results suggest that hyperammonemia induces TNF-a in glial cells and that TNF-a released by glial cells activates TNFR1 in Purkinje neurons, leading to NF-κB nuclear translocation and the induction of TNF-a expression, which may contribute to the neurological alterations observed in hyperammonemia and hepatic encephalopathy.

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Section: Discussionmentioning

confidence: 99%

Sustained hyperammonemia induces TNF-a IN Purkinje neurons by activating the TNFR1-NF-κB pathway

Balzano

Arenas

Dadsetan

et al. 2020

J Neuroinflammation

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“…The NF-κB pathway is a major inflammatory pathway involved in activation of the innate and adaptive immune responses essential for e.g., generation of T-cell and B-cells. The pathway is constitutively active in many inflammatory disorders of the white matter [90,134]. In vitro, astrocytes upregulate NF-κB in response to pro-inflammatory cytokines such as IL-17, IL-1β, and TNF-α [90,135].…”

Section: Astrocytes In Neuroinflammationmentioning

confidence: 99%

“…Subtle white matter changes are found in neurodegenerative diseases as early as pre-clinical AD where the NF-κB pathway could play a role in exacerbating inflammatory signaling [139]. Intervention in this pathway is effective, as demonstrated by the MS drug laquinimod, which inhibits astrocytic NF-κB expression [4,134]. NF-κB signalling represents an important inflammatory pathway in various neurological disorders that is frequently used by astrocytes to exacerbate inflammation.…”

Section: Astrocytes In Neuroinflammationmentioning

confidence: 99%

Astrocyte and Oligodendrocyte Cross-Talk in the Central Nervous System

Nutma

Gent

Amor

et al. 2020

Cells

120

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Over the last decade knowledge of the role of astrocytes in central nervous system (CNS) neuroinflammatory diseases has changed dramatically. Rather than playing a merely passive role in response to damage it is clear that astrocytes actively maintain CNS homeostasis by influencing pH, ion and water balance, the plasticity of neurotransmitters and synapses, cerebral blood flow, and are important immune cells. During disease astrocytes become reactive and hypertrophic, a response that was long considered to be pathogenic. However, recent studies reveal that astrocytes also have a strong tissue regenerative role. Whilst most astrocyte research focuses on modulating neuronal function and synaptic transmission little is known about the cross-talk between astrocytes and oligodendrocytes, the myelinating cells of the CNS. This communication occurs via direct cell-cell contact as well as via secreted cytokines, chemokines, exosomes, and signalling molecules. Additionally, this cross-talk is important for glial development, triggering disease onset and progression, as well as stimulating regeneration and repair. Its critical role in homeostasis is most evident when this communication fails. Here, we review emerging evidence of astrocyte-oligodendrocyte communication in health and disease. Understanding the pathways involved in this cross-talk will reveal important insights into the pathogenesis and treatment of CNS diseases.

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“…IκBα, the negative regulator of NFκB and a known LDE sensor, may also be targeted by DMF, although direct modification has not yet been demonstrated (Dou et al, 2012). Overall, the relevance of NFκB signaling in DMF's MOA has not been explicitly evaluated experimentally in MS patients or animal models, although the relative benefits, drawbacks, and challenges of modulation of this pathway in MS have been reviewed extensively (Leibowitz and Yan, 2016).…”

Section: P65 and Iκbαmentioning

confidence: 99%

Electrophile Signaling and Emerging Immuno- and Neuro-modulatory Electrophilic Pharmaceuticals

Poganik

Aye

2020

Front. Aging Neurosci.

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With a lipid-rich environment and elevated oxygen consumption, the central nervous system (CNS) is subject to intricate regulation by lipid-derived electrophiles (LDEs). Investigations into oxidative damage and chronic LDE generation in neural disorders have spurred the development of tools that can detect and catalog the gamut of LDE-adducted proteins. Despite these advances, deconstructing the precise consequences of individual protein-specific LDE modifications remained largely impossible until recently. In this perspective, we first overview emerging toolsets that can decode electrophile-signaling events in a protein/context-specific manner, and how the accumulating mechanistic insights brought about by these tools have begun to offer new means to modulate pathways relevant to multiple sclerosis (MS). By surveying the latest data surrounding the blockbuster MS drug dimethyl fumarate that functions through LDE-signaling-like mechanisms, we further provide a vision for how chemical biology tools probing electrophile signaling may be leveraged toward novel interventions in CNS disease.

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

Cited by 88 publications

References 219 publications

Sustained hyperammonemia induces TNF-a IN Purkinje neurons by activating the TNFR1-NF-κB pathway

Sustained hyperammonemia induces TNF-a IN Purkinje neurons by activating the TNFR1-NF-κB pathway

Astrocyte and Oligodendrocyte Cross-Talk in the Central Nervous System

Electrophile Signaling and Emerging Immuno- and Neuro-modulatory Electrophilic Pharmaceuticals

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