Abstract
BackgroundTumor necrosis factor (TNF) is associated with several neurodegenerative disorders including multiple sclerosis (MS). Although TNF-targeted therapies have been largely unsuccessful in MS, recent preclinical data suggests selective soluble TNF inhibition can promote remyelination. This has renewed interest in regulation of TNF signaling in demyelinating disease, especially given the limited treatment options for progressive MS. Using a mouse model of progressive MS, this study evaluates the effects of sustained TNF on oligodendrocyte (OLG) apoptosis and OLG precursor cell (OPC) differentiation.MethodsInduction of experimental autoimmune encephalomyelitis (EAE) in transgenic mice expressing a dominant-negative interferon-γ receptor under the human glial fibrillary acidic protein promoter (GFAPγR1Δ) causes severe non-remitting disease associated with sustained TNF. Therapeutic effects in GFAPγR1Δ mice treated with anti-TNF compared to control antibody during acute EAE were evaluated by assessing demyelinating lesion size, remyelination, OLG apoptosis, and OPC differentiation.ResultsMore severe and enlarged demyelinating lesions in GFAPγR1Δ compared to wild-type (WT) mice were associated with increased OLG apoptosis and reduced differentiated CC1+Olig2+ OLG within lesions, as well as impaired upregulation of TNF receptor-2, suggesting impaired OPC differentiation. TNF blockade during acute EAE in GFAPγR1Δ both limited OLG apoptosis and enhanced OPC differentiation consistent with reduced lesion size and clinical recovery. TNF neutralization further limited increasing endothelin-1 (ET-1) expression in astrocytes and myeloid cells noted in lesions during disease progression in GFAPγR1Δ mice, supporting inhibitory effects of ET-1 on OPC maturation.ConclusionOur data implicate that IFNγ signaling to astrocytes is essential to limit a detrimental positive feedback loop of TNF and ET-1 production, which increases OLG apoptosis and impairs OPC differentiation. Interference of this cycle by TNF blockade promotes repair independent of TNFR2 and supports selective TNF targeting to mitigate progressive forms of MS.
Highlights
Tumor necrosis factor (TNF) is associated with several neurodegenerative disorders including multiple sclerosis (MS)
TNF neutralization reduces demyelinating lesion size during progressive EAE Monoclonal antibody-mediated TNF blockade in GFAPγR1Δ mice developing progressive EAE was previously shown to be therapeutic as evidenced by substantially reduced clinical disease, inflammation, and demyelination [28]
Lesion size in GFAPγR1Δ mice undergoing acute EAE was slightly reduced compared to WT mice, it was significantly increased during disease progression, consistent with previous results [26,27,28]
Summary
Tumor necrosis factor (TNF) is associated with several neurodegenerative disorders including multiple sclerosis (MS). TNF-targeted therapies have been largely unsuccessful in MS, recent preclinical data suggests selective soluble TNF inhibition can promote remyelination This has renewed interest in regulation of TNF signaling in demyelinating disease, especially given the limited treatment options for progressive MS. Irrespective of initially effective treatment options prolonging the onset of severe neurological cognitive and motor impairments in patients with RR-MS, therapeutic interventions fail in patients with primary and secondary progressive (P)-MS This disease state is characterized by sparse inflammation, lack of remyelination, mitochondrial dysfunction, axonal loss, and CNS atrophy [1,2,3,4,5,6,7, 14]. Astrocytes, interferon γ (IFNγ), and tumor necrosis factor (TNF) individually are all known to promote inflammation and mediate neuroprotective functions in demyelinating disease [17,18,19,20,21]
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