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

Journal of Neuroinflammation
Alice Valentin-TorresStephen A Stohlman

Abstract

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. 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. 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 addit...Continue Reading

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Citations

Mar 25, 2017·Current Neurology and Neuroscience Reports·Elissavet Kemanetzoglou, Elisabeth Andreadou
Feb 9, 2017·Journal of Neuroinflammation·Catherine W M OngJon S Friedland
Feb 14, 2020·Nature·Michael A WheelerFrancisco J Quintana
Oct 24, 2017·Scientific Reports·Sophie SteelandClaude Libert
Apr 11, 2019·Frontiers in Pharmacology·Jiaying WangQiaojun He
Dec 28, 2019·International Journal of Molecular Sciences·Mario Stampanoni BassiFabio Buttari
Jun 18, 2017·Frontiers in Neurology·Ahmed AbdelhakHayrettin Tumani
Aug 11, 2019·Nature Reviews. Drug Discovery·Simon FaissnerV Wee Yong
Oct 18, 2020·Cells·Diego FresegnaAntonietta Gentile
Jan 29, 2021·The Journal of Immunology : Official Journal of the American Association of Immunologists·Arnaud HuardAndreas Weigert

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Methods Mentioned

BETA
transgenic
FACS
ELISA
PCR
Assay
flow cytometry
PMA

Software Mentioned

SigmaStat
Image
FACS Diva
Aperio
Pro

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