Connecting Immune Cell Infiltration to the Multitasking Microglia Response and TNF Receptor 2 Induction in the Multiple Sclerosis Brain

Veroni, Caterina; Serafini, Barbara; Rosicarelli, Barbara; Fagnani, Corrado; Aloisi, Francesca; Agresti, Cristina

doi:10.3389/fncel.2020.00190

Cited by 15 publications

(10 citation statements)

References 104 publications

(186 reference statements)

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“…IFNγ and TNFα have been shown to induce RBP mislocalization in cell lines [27,40]. In MS tissues, there is elevated expression of IFNγ and TNFα and their receptors in immune cell infiltrates, neurons, and oligodendrocytes in grey and white matter [44,47]. These data suggest that the presence of pro-inflammatory cytokines within these areas and the cells themselves may contribute to RBP dysfunction and, consequently, neuronal damage.…”

Section: Discussionmentioning

confidence: 92%

Pro-Inflammatory Cytokines and Antibodies Induce hnRNP A1 Dysfunction in Mouse Primary Cortical Neurons

Hamilton

Salapa

et al. 2021

Brain Sciences

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Multiple sclerosis (MS) is an inflammatory disease of the central nervous system with a significant neurodegenerative component. Dysfunctional RNA-binding proteins (RBPs) are causally linked to neuronal damage and are a feature of MS, including the mislocalization of the RBP heterogeneous nuclear ribonucleoprotein A1 (A1). Here, we show that primary neurons exposed to pro-inflammatory cytokines and anti-A1 antibodies, both characteristic of an MS autoimmune response, displayed increased A1 mislocalization, stress granule formation, and decreased neurite length, a marker of neurodegeneration. These findings illustrate a significant relationship between secreted immune factors, A1 dysfunction, and neuronal damage in a disease-relevant model system.

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Section: Discussionmentioning

confidence: 92%

Pro-Inflammatory Cytokines and Antibodies Induce hnRNP A1 Dysfunction in Mouse Primary Cortical Neurons

Hamilton

Salapa

et al. 2021

Brain Sciences

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“…More recently, Veroni and colleagues (2020) found a significant upregulation of TNFR1 in subpial GM lesions and in both active and normal appearing white matter lesions. Interestingly, the authors found an even more increased expression of TNFR2 mRNA in white matter lesions, including chronic active lesions, without changes in the GM and in normal white matter areas surrounding the rim of active lesions, suggesting reparative mechanisms in the areas close to damaged zones [ 154 ].…”

Section: Evidence For Tnf Involvement In Pathological Hallmarks Ofmentioning

confidence: 99%

Re-Examining the Role of TNF in MS Pathogenesis and Therapy

Fresegna

Bullitta

Musella

et al. 2020

Cells

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Multiple sclerosis (MS) is a common neurological disorder of putative autoimmune origin. Clinical and experimental studies delineate abnormal expression of specific cytokines over the course of the disease. One major cytokine that has been shown to play a pivotal role in MS is tumor necrosis factor (TNF). TNF is a pleiotropic cytokine regulating many physiological and pathological functions of both the immune system and the central nervous system (CNS). Convincing evidence from studies in human and experimental MS have demonstrated the involvement of TNF in various pathological hallmarks of MS, including immune dysregulation, demyelination, synaptopathy and neuroinflammation. However, due to the complexity of TNF signaling, which includes two-ligands (soluble and transmembrane TNF) and two receptors, namely TNF receptor type-1 (TNFR1) and type-2 (TNFR2), and due to its cell- and context-differential expression, targeting the TNF system in MS is an ongoing challenge. This review summarizes the evidence on the pathophysiological role of TNF in MS and in different MS animal models, with a special focus on pharmacological treatment aimed at controlling the dysregulated TNF signaling in this neurological disorder.

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“…Increasing evidence from in vitro and in vivo studies points to a crucial role of TNF signalling in mediating both WM and GM pathology. 25 – 28 CSF TNF levels in progressive MS patients have been linked to altered synaptic transmission, with exacerbation of glutamatergic transmission and neuronal damage when incubating CSF with corticostriatal slices. 29 , 30 Recently, persistent expression of CSF TNF along with IFN gamma has been described as a potent inducer of meningeal inflammation and subpial demyelination in the myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) model.…”

Section: Discussionmentioning

confidence: 99%

CSF TNF and osteopontin levels correlate with the response to dimethyl fumarate in early multiple sclerosis

Marastoni

Pisani

Schiavi

et al. 2022

Ther Adv Neurol Disord

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Background: Disease activity in the first years after a diagnosis of relapsing-remitting multiple sclerosis (RRMS) is a negative prognostic factor for long-term disability. Markers of both clinical and radiological responses to disease-modifying therapies (DMTs) are advocated. Objective: The objective of this study is to estimate the value of cerebrospinal fluid (CSF) inflammatory markers at the time of diagnosis in predicting the disease activity in treatment-naïve multiple sclerosis (MS) patients exposed to dimethyl fumarate (DMF). Methods: In total, 48 RRMS patients (31 females/17 males) treated with DMF after the diagnosis were included in this 2-year longitudinal study. All patients underwent a CSF examination, regular clinical and 3T magnetic resonance imaging (MRI) scans that included the assessment of white matter (WM) lesions, cortical lesions (CLs) and global cortical thickness. CSF levels of 10 pro-inflammatory markers – CXCL13 [chemokine (C-X-C motif) ligand 13 or B lymphocyte chemoattractant], CXCL12 (stromal cell-derived factor or C-X-C motif chemokine 12), tumour necrosis factor (TNF), APRIL (a proliferation-inducing ligand, or tumour necrosis factor ligand superfamily member 13), LIGHT (tumour necrosis factor ligand superfamily member 14 or tumour necrosis factor superfamily member 14), interferon (IFN) gamma, interleukin 12 (IL-12), osteopontin, sCD163 [soluble-CD163 (cluster of differentiation 163)] and Chitinase3-like1 – were assessed using immune-assay multiplex techniques. The combined three-domain status of ‘no evidence of disease activity’ (NEDA-3) was defined by no relapses, no disability worsening and no MRI activity, including CLs. Results: Twenty patients (42%) reached the NEDA-3 status; patients with disease activity showed higher CSF TNF ( p = 0.009), osteopontin ( p = 0.005), CXCL12 ( p = 0.037), CXCL13 ( p = 0.040) and IFN gamma levels ( p = 0.019) compared with NEDA-3 patients. After applying a random forest approach, TNF and osteopontin revealed the most important variables associated with the NEDA-3 status. Six molecules that emerged at the random forest approach were added in a multivariate regression model with demographic, clinical and MRI measures of WM and grey matter damage as independent variables. TNF levels confirmed to be associated with the absence of disease activity: odds ratio (OR) = 0.25, CI% = 0.04–0.77. Conclusion: CSF inflammatory markers may provide prognostic information in predicting disease activity in the first years after DMF initiation. CSF TNF levels are a possible candidate in predicting treatment response, in addition to clinical, demographic and MRI variables.

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Connecting Immune Cell Infiltration to the Multitasking Microglia Response and TNF Receptor 2 Induction in the Multiple Sclerosis Brain

Cited by 15 publications

References 104 publications

Pro-Inflammatory Cytokines and Antibodies Induce hnRNP A1 Dysfunction in Mouse Primary Cortical Neurons

Pro-Inflammatory Cytokines and Antibodies Induce hnRNP A1 Dysfunction in Mouse Primary Cortical Neurons

Re-Examining the Role of TNF in MS Pathogenesis and Therapy

CSF TNF and osteopontin levels correlate with the response to dimethyl fumarate in early multiple sclerosis

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