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Tumor necrosis factor receptor 2 activation elicits sex-specific effects on cortical myelin proteins and functional recovery in a model of multiple sclerosis.

ABSTRACT: Multiple sclerosis (MS), a demyelinating autoimmune disease of the central nervous system (CNS), predominately affects females compared to males. Tumor necrosis factor (TNF), a pro-inflammatory cytokine, signaling through TNF receptor 1 contributes to inflammatory disease pathogenesis. In contrast, TNF receptor 2 signaling is neuroprotective. Current anti-TNF MS therapies are shown to be detrimental to patients due to pleiotropic effects on both pro- and anti-inflammatory functions. Using a non-pertussis toxin (nPTX) experimental autoimmune encephalomyelitis (EAE) model in C57BL/6 mice, we systemically administered a TNFR2 agonist (p53-sc-mTNF_R2) to investigate behavioral and pathophysiological changes in both female and male mice. Our data shows that TNFR2 activation alleviates motor and sensory symptoms in females. However, in males, the agonist only alleviates sensory symptoms and not motor. nPTX EAE induction in TNFR2 global knockout mice caused exacerbated motor symptoms in females along with an earlier day of onset, but not in males. Our data demonstrates that TNFR2 agonist efficacy is sex-specific for alleviation of motor symptoms, however, it effectively reduces mechanical hypersensitivity in both females and males. Altogether, these data support the therapeutic promise TNFR2 agonism holds as an MS therapeutic and, more broadly, to treat central neuropathic pain.

SUBMITTER: Nguyen KL

PROVIDER: S-EPMC10923072 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Tumor necrosis factor receptor 2 activation elicits sex-specific effects on cortical myelin proteins and functional recovery in a model of multiple sclerosis.

Nguyen Kayla L KL Bhatt Ishaan J IJ Gupta Shruti S Showkat Nazaf N Swanson Kathryn A KA Fischer Roman R Kontermann Roland E RE Pfizenmaier Klaus K Bracchi-Ricard Valerie V Bethea John R JR

Brain research bulletin 20240120

Multiple sclerosis (MS), a demyelinating autoimmune disease of the central nervous system (CNS), predominately affects females compared to males. Tumor necrosis factor (TNF), a pro-inflammatory cytokine, signaling through TNF receptor 1 contributes to inflammatory disease pathogenesis. In contrast, TNF receptor 2 signaling is neuroprotective. Current anti-TNF MS therapies are shown to be detrimental to patients due to pleiotropic effects on both pro- and anti-inflammatory functions. Using a non- ...[more]

PMID: 38246200

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Project description:Sustained exposure to pro-inflammatory cytokines in the leptomeninges is thought to play a major role in the pathogenetic mechanisms leading to cortical pathology in multiple sclerosis (MS). Although the molecular mechanisms underlying neurodegeneration in the grey matter remain unclear, several lines of evidence suggest a prominent role for tumour necrosis factor (TNF). Using cortical grey matter tissue blocks from post-mortem brains from 28 secondary progressive MS subjects and ten non-neurological controls, we describe an increase in expression of multiple steps in the TNF/TNF receptor 1 signaling pathway leading to necroptosis, including the key proteins TNFR1, FADD, RIPK1, RIPK3 and MLKL. Activation of this pathway was indicated by the phosphorylation of RIPK3 and MLKL and the formation of protein oligomers characteristic of necrosomes. In contrast, caspase-8 dependent apoptotic signaling was decreased. Upregulation of necroptotic signaling occurred predominantly in macroneurons in cortical layers II-III, with little expression in other cell types. The presence of activated necroptotic proteins in neurons was increased in MS cases with prominent meningeal inflammation, with a 30-fold increase in phosphoMLKL+ neurons in layers I-III. The density of phosphoMLKL+ neurons correlated inversely with age at death, age at progression and disease duration. In vivo induction of chronically elevated TNF and INFγ levels in the CSF in a rat model via lentiviral transduction in the meninges, triggered inflammation and neurodegeneration in the underlying cortical grey matter that was associated with increased neuronal expression of TNFR1 and activated necroptotic signaling proteins. Exposure of cultured primary rat cortical neurons to TNF induced necroptosis when apoptosis was inhibited. Our data suggest that neurons in the MS cortex are dying via TNF/TNFR1 stimulated necroptosis rather than apoptosis, possibly initiated in part by chronic meningeal inflammation. Neuronal necroptosis represents a pathogenetic mechanism that is amenable to therapeutic intervention at several points in the signaling pathway.

Project description:BackgroundMyelin water imaging (MWI) is a myelin-specific technique, which has great potential for the assessment of demyelination and remyelination. This study develops a new MWI method, which employs a short repetition time adiabatic inversion recovery (STAIR) technique in combination with a commonly used fast spin echo (FSE) sequence and provides quantification of myelin water (MW) fractions.MethodWhole-brain MWI was performed using the short repetition time adiabatic inversion recovery prepared-fast spin echo (STAIR-FSE) technique on eight healthy volunteers (mean age: 38±14 years, four-males) and seven patients with multiple sclerosis (MS) (mean age: 53.7±8.7 years, two-males) on a 3T clinical magnetic resonance imaging scanner. To facilitate the quantification of apparent myelin water fraction (aMWF), a proton density-weighted FSE was also used during the scans to allow total water imaging. The aMWF measurements of MS lesions and normal-appearing white matter (NAWM) regions in MS patients were compared with those measured in normal white matter (NWM) regions in healthy volunteers. Both the analysis of variance (ANOVA) test and paired comparison were performed for the comparison.ResultsThe MW in the whole-brain was selectively imaged and quantified using the STAIR-FSE technique in all participants. MS lesions showed much lower signal intensities than NAWM in the STAIR-FSE images. ANOVA analysis revealed a significant difference in the aMWF measurements between the three groups. Moreover, the aMWF measurements in MS lesions were significantly lower than those in both NWM of healthy volunteers and NAWM of MS patients. Lower aMWF measurements in NAWM were also found in comparison with those in NWM.ConclusionsThe STAIR-FSE technique is capable of measuring aMWF values for the indirect detection of myelin loss in MS, thus facilitating clinical translation of whole brain MWI and quantification, which show great potential for the detection and evaluation of changes in myelin in the brain of patients with MS for future larger cohort studies.

Dataset Information

Tumor necrosis factor receptor 2 activation elicits sex-specific effects on cortical myelin proteins and functional recovery in a model of multiple sclerosis.

Publications

Tumor necrosis factor receptor 2 activation elicits sex-specific effects on cortical myelin proteins and functional recovery in a model of multiple sclerosis.

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