Inhibition of soluble tumour necrosis factor is therapeutic in experimental autoimmune encephalomyelitis and promotes axon preservation and remyelination

Abstract

Tumour necrosis factor is linked to the pathophysiology of various neurodegenerative disorders including multiple sclerosis. Tumour necrosis factor exists in two biologically active forms, soluble and transmembrane. Here we show that selective inhibition of soluble tumour necrosis factor is therapeutic in experimental autoimmune encephalomyelitis. Treatment with XPro1595, a selective soluble tumour necrosis factor blocker, improves the clinical outcome, whereas non-selective inhibition of both forms of tumour necrosis factor with etanercept does not result in protection. The therapeutic effect of XPro1595 is associated with axon preservation and improved myelin compaction, paralleled by increased expression of axon-specific molecules (e.g. neurofilament-H) and reduced expression of non-phosphorylated neurofilament-H which is associated with axon damage. XPro1595-treated mice show significant remyelination accompanied by elevated expression of myelin-specific genes and increased numbers of oligodendrocyte precursors. Immunohistochemical characterization of tumour necrosis factor receptors in the spinal cord following experimental autoimmune encephalomyelitis shows tumour necrosis factor receptor 1 expression in neurons, oligodendrocytes and astrocytes, while tumour necrosis factor receptor 2 is localized in oligodendrocytes, oligodendrocyte precursors, astrocytes and macrophages/microglia. Importantly, a similar pattern of expression is found in post-mortem spinal cord of patients affected by progressive multiple sclerosis, suggesting that pharmacological modulation of tumour necrosis factor receptor signalling may represent an important target in affecting not only the course of mouse experimental autoimmune encephalomyelitis but human multiple sclerosis as well. Collectively, our data demonstrate that selective inhibition of soluble tumour necrosis factor improves recovery following experimental autoimmune encephalomyelitis, and that signalling mediated by transmembrane tumour necrosis factor is essential for axon and myelin preservation as well as remyelination, opening the possibility of a new avenue of treatment for multiple sclerosis.

Altered Expression of Oligodendrocyte and Neuronal Marker Genes Predicts the Clinical Onset of Autoimmune Encephalomyelitis and Indicates the Effectiveness of Multiple Sclerosis–Directed Therapeutics

“…For example, EAEinduced changes in expression of H2-Ab1, Mbp, Nrg1, Snap25, and Grin1 were prevented in the presymptomatic phase of disease by XPro1595 administration. We (37) and other investigators (53) showed that XPro1595 protects mice against clinical MOGinduced EAE when administered in prophylactic and therapeutic protocols. There, protection was not paralleled by a reduction in inflammatory lesions in the spinal cord, but with reduced overall neuroinflammation and preservation of myelin and neuron integrity during full-blown disease.…”

Essential protective role of tumor necrosis factor receptor 2 in neurodegeneration

“…In support of this finding, we here provide compelling evidence in an in vivo model of NMDAinduced acute neuronal lesions that abrogation of complete TNF signaling by blocking both TNFRs is not protective, because mounting of a neuroprotective TNFR2-dependent response is prevented. However, preclinical studies in the experimental autoimmune encephalomyelitis (EAE) model (36)(37)(38) or a mouse model of spinal cord injury (39) revealed that selective neutralization of sTNF/TNFR1 signaling is neuroprotective. Of note, in the EAE model, systemic application of TNFR1-blocking antibodies proved to be therapeutically effective (40).…”

Peripheral elevation of TNF-α leads to early synaptic abnormalities in the mouse somatosensory cortex in experimental autoimmune encephalomyelitis

“…The increased production of proinflammatory cytokines and infiltration of peripheral immune cells into the central nervous system (CNS) are closely associated with neuronal damage in the spinal cord and many brain regions (6)(7)(8)(9)(10). Elevation of several cytokines such as TNF-α and IFN-γ precedes infiltration of peripheral immune cells and could have a significant impact on neuronal function (11)(12)(13)(14)(15)(16)(17)(18)(19), potentially contributing to early sensory and cognitive impairments.…”

“…A dominant negative TNF inhibitor, XPro1595, blocks the effects of solTNF to selectively decrease the activation of TNFR1 (35,36). Recently, decreased activation of TNFR1 via XPro1595 has been shown to promote axonal integrity and improve clinical outcome of mice with EAE (10).…”