TRAIL receptor 2 immunofluorescence in the mouse hippocampus. Image courtesy of F. Zipp, Institute of Neuroimmunology, Humboldt University, Berlin, Germany.

A protein that has well-described anti-inflammatory effects in animal models of multiple sclerosis (MS) might contribute to brain cell death in the disorder, according to the results of a new study. The finding offers the interesting possibility that suppressing the actions of TRAIL (tumour necrosis factor-related apoptosis-inducing ligand) in the CNS, while boosting its actions in the periphery, could improve clinical outcomes in MS.

Experimental autoimmune encephalomyelitis (EAE) has been used for decades to model immune events in the inflammatory, demyelinating disease MS. Previous studies have shown that TRAIL can inhibit the activity of autoreactive T cells — the mediators of pathogenesis in EAE — and that peripheral blockade of TRAIL can worsen EAE. What's more, TRAIL is upregulated in patients with MS who respond positively to interferon-β, an immunomodulatory treatment that is widely used in MS. But TRAIL is also known to induce apoptosis in human neurons and oligodendroglia in slice culture. Could this 'death ligand' have negative, neurodegenerative effects in EAE and MS?

To selectively block the actions of TRAIL in the brains of mice with EAE, Aktas and colleagues used TRAIL receptor 2 (TRAILR2 or DR5) fused to the antibody fragment Fc. Neuronal apoptosis in brainstem motor areas was markedly reduced in mice treated with the fusion protein, which was injected intracisternally after EAE had been triggered. Clinical disease scores also fell after DR5:Fc injection. The researchers went on to show that TRAIL-deficient, myelin-specific T cells were less able to trigger EAE than were myelin-reactive cells from wild-type animals. Conversely, they found that the intracerebral delivery of TRAIL before or at the onset of EAE increased disease severity. Finally, TRAIL was shown to be a mediator of neuronal cell death induced by encephalitogenic T cells in organotypic brain slices.

By using EAE to model the neurodegenerative aspects of MS, Aktas and colleagues have shown that TRAIL contributes to neuronal apoptosis during autoimmune neuroinflammation. Could selectively inhibiting TRAIL in the CNS be of benefit to patients with MS? An important step in answering this question will be to determine whether the neuronal expression of TRAIL receptors is increased in the brains of patients. We await with interest further insights into the divergent functions of TRAIL.