Sustained TNF production by central nervous system infiltrating macrophages promotes progressive autoimmune
Alice Valentin-Torres1, Carine Savarin2, David R Hinton3
1Department of Neurosciences NC-30, Lerner Research Institute, The Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH, 44195, USA. valenta@ccf.org.
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.
Insights
Targeting tumor necrosis factor (TNF) in experimental autoimmune encephalomyelitis (EAE) reduced disability and mortality. This study shows sustained TNF exacerbates central nervous system (CNS) inflammation and damage in progressive EAE.
Area of Science:
- Neuroimmunology
- Autoimmune Diseases
Background:
- Tumor necrosis factor (TNF) plays a role in multiple sclerosis (MS) and its model, experimental autoimmune encephalomyelitis (EAE).
- The precise role of TNF in progressive MS and EAE remains unclear.
- This study investigates TNF's role in exacerbating CNS pathology and inflammation in a progressive EAE model.
Purpose of the Study:
- To evaluate the role of sustained TNF in exacerbating central nervous system (CNS) pathology and inflammation during progressive EAE.
- To assess the therapeutic effects of anti-TNF treatment on disability, demyelination, CNS inflammation, and blood-brain barrier (BBB) permeability.
Main Methods:
- A progressive EAE model was established using myelin oligodendrocyte glycoprotein (MOG) peptide immunization in GFAPγR1∆ mice.
- Mice were treated with anti-TNF or control monoclonal antibody during acute disease.
- Therapeutic effects were monitored for clinical disability, demyelination, CNS inflammation, and BBB permeability.
Main Results:
- TNF was sustained in infiltrating macrophages.
- Anti-TNF treatment significantly decreased clinical disability and mortality within 7 days.
- TNF neutralization reduced myelin loss, leukocyte infiltration, macrophage activation, mitigated CNS inflammation, restored BBB integrity, and enhanced CNS anti-inflammatory responses.
Conclusions:
- Sustained TNF production by macrophages in progressive EAE worsens disease severity.
- TNF exacerbates disease by promoting inflammation and disrupting BBB integrity.
- Neutralizing TNF counteracts these effects, promoting an anti-inflammatory environment necessary for disease remission.
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