Tumor Necrosis Factor α Influences Phenotypic Plasticity and Promotes Epigenetic Changes in Human Basal Forebrain Cholinergic Neuroblasts

Abstract

TNFα is the main proinflammatory cytokine implicated in the pathogenesis of neurodegenerative disorders, but it also modulates physiological functions in both the developing and adult brain. In this study, we investigated a potential direct role of TNFα in determining phenotypic changes of a recently established cellular model of human basal forebrain cholinergic neuroblasts isolated from the nucleus basalis of Meynert (hfNBMs). Exposing hfNBMs to TNFα reduced the expression of immature markers, such as nestin and β-tubulin III, and inhibited primary cilium formation. On the contrary, TNFα increased the expression of TNFα receptor TNFR2 and the mature neuron marker MAP2, also promoting neurite elongation. Moreover, TNFα affected nerve growth factor receptor expression. We also found that TNFα induced the expression of DNA-methylation enzymes and, accordingly, downregulated genes involved in neuronal development through epigenetic mechanisms, as demonstrated by methylome analysis. In summary, TNFα showed a dual role on hfNBMs phenotypic plasticity, exerting a negative influence on neurogenesis despite a positive effect on differentiation, through mechanisms that remain to be elucidated. Our results help to clarify the complexity of TNFα effects in human neurons and suggest that manipulation of TNFα signaling could provide a potential therapeutic approach against neurodegenerative disorders.

Perspective: Treatment for Disease Modification in Chronic Neurodegeneration

“…Examples are mitochondriopathy, dysfunction of the ubiquitin/proteasome system, oxidative and nitrosative stress, dysregulation of heat shock response, altered iron metabolism and vesicular transport systems, apoptosis, necrosis, autophagy, microglial activation combined with neuroinflammation [ 23 , 62 , 112 ]. Therapeutic concepts were, and are, developed based on findings, such as that the pro-inflammatory TNF-alpha cytokine is able to modify neuronal plasticity, maturation, and function of human cholinergic neurons also by epigenetic mechanisms [ 61 ]. All of these disease related alterations and their possible therapies will consequently change neurotransmission pathways [ 113 ].…”

“…Post mortem neuropathological brain investigations describe an accumulation of plaques and tangles with β-amyloid- and/or tau protein pathology in AD. Dystrophic neuritis, astrogliosis, neuropil threads, and microglial activation with neuroinflammation has also been reported [ 22 , 23 , 24 , 61 ]. These changes result in an acetylcholine deficit, which is mainly looked upon as responsible for the cognitive impairment.…”

Neuroinflammation: Integrated Nervous Tissue Response through Intercellular Interactions at the “Whole System” Scale

“…Of note, IL-33 released by astrocytes has been suggested to modulate typical microglia activities such as the pruning of synapses in mouse embryos during maturation [ 50 ] and modulation of synaptic plasticity in adult mice (16 weeks old) [ 104 ]. In cell cultures, TNF-α has been demonstrated to promote astrogenesis from human neural progenitors [ 172 ] and the maturation of human neuroblasts [ 173 ]. These data indicate that cytokines may be involved, either as effectors or mediators, in dynamic lifespan changes of the CNS.…”

Breaching the Blood–Brain Tumor Barrier for Tumor Therapy

“…These encouraging results contrast with limited benefit achieved with regadenoson and cereport, which may be explained, at least in part, by the widespread distribution of receptors to the latter drugs throughout the endothelial lining of the organism, whereas CD13 expression is more restricted to angiogenic/inflamed endothelia, including tumor blood vessels. While the use of this targeted version of TNF has yielded very positive results, a note of caution regarding the use of TNF in the CNS should be sounded in consideration of some recent results showing the negative effects of TNF on neurogenesis [ 81 ]. It is doubtful, however, that this may represent a major concern for NGR-TNF, which is delivered at very low doses to the brain tumor vasculature rather than to the neuronal components of the CNS.…”