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Open Access 01-12-2016 | Research

Sustained TNF production by central nervous system infiltrating macrophages promotes progressive autoimmune encephalomyelitis

Authors: Alice Valentin-Torres, Carine Savarin, David R. Hinton, Timothy W. Phares, Cornelia C. Bergmann, Stephen A. Stohlman

Published in: Journal of Neuroinflammation | Issue 1/2016

Abstract

Background

Tumor necrosis factor (TNF) has pleiotropic functions during both the demyelinating autoimmune disease multiple sclerosis (MS) and its murine model experimental autoimmune encephalomyelitis (EAE). How TNF regulates disability during progressive disease remains unresolved. Using a progressive EAE model characterized by sustained TNF and increasing morbidity, this study evaluates the role of unregulated TNF in exacerbating central nervous system (CNS) pathology and inflammation.

Methods

Progressive MS was mimicked by myelin oligodendrocyte glycoprotein (MOG) peptide immunization of mice expressing a dominant negative IFN-γ receptor alpha chain under the human glial fibrillary acidic protein promoter (GFAPγR1∆). Diseased GFAPγR1∆ mice were treated with anti-TNF or control monoclonal antibody during acute disease to monitor therapeutic effects on sustained disability, demyelination, CNS inflammation, and blood brain barrier (BBB) permeability.

Results

TNF was specifically sustained in infiltrating macrophages. Anti-TNF treatment decreased established clinical disability and mortality rate within 7 days. Control of disease progression was associated with a decline in myelin loss and leukocyte infiltration, as well as macrophage activation. In addition to mitigating CNS inflammation, TNF neutralization restored BBB integrity and enhanced CNS anti-inflammatory responses.

Conclusions

Sustained TNF production by infiltrating macrophages associated with progressive EAE exacerbates disease severity by promoting inflammation and disruption of BBB integrity, thereby counteracting establishment of an anti-inflammatory environment required for disease remission.

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Title: Sustained TNF production by central nervous system infiltrating macrophages promotes progressive autoimmune encephalomyelitis
Authors: Alice Valentin-Torres
Carine Savarin
David R. Hinton
Timothy W. Phares
Cornelia C. Bergmann
Stephen A. Stohlman
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2016
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-016-0513-y

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Sustained TNF production by central nervous system infiltrating macrophages promotes progressive autoimmune encephalomyelitis

Abstract

Background

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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