Background
Inflammation of the central nervous system (CNS) in MS is responsible for damage to the myelin sheath surrounding nerve fibres. This, in turn, impairs the ability for nerves to communicate with one another, leading to a host of neurological symptoms experienced by affected individuals. The blood-brain barrier normally acts as a gate that keeps harmful inflammatory cells and molecules out of the CNS. One molecule in particular, a cytokine named interleukin-17 (IL-17), can promote a strong inflammatory response upon infiltrating the CNS. Inappropriate invasion of IL-17 and other immune factors into the CNS has been demonstrated to be a key step towards the development of MS.
In a study published this month in the journal Molecular Psychiatry, a team of researchers explored the role of the anti-inflammatory factor developmental endothelial locus-1 (Del-1) as a potential “gatekeeper” that prevents inflammatory cells from entering and damaging the CNS. In an earlier study, this research group showed that Del-1 can protect against periondontitis – an inflammatory disease associated with aging – by opposing the actions of inflammatory molecules like IL-17. These results led them to speculate that Del-1 may also be a strong candidate for counteracting harmful inflammation in MS.
The Study
In this elegant study, the authors tested the effects of Del-1 on disease severity and inflammation in mice with an MS-like disease. Specifically, they wanted to find out if lower levels and subsequent reduced activity of Del-1 was associated with MS disease.
Firstly, to determine the relationship between Del-1 and MS, researchers measured levels of Del-1 in the spinal cords of mice with the MS-like disease and compared them to healthy mice. To switch off Del-1, the authors produced genetic knockout mice and compared them to their littermates who had a functioning Del-1 gene. To assess changes in disease severity, they measured the amount of demyelination (deterioration of the myelin sheath) and damage to the nerve fibres. They also examined how the absence of Del-1 affected inflammation, including the levels of IL-17, breakdown of the blood-brain barrier, and infiltration of immune cells into the CNS. Their final goal was to see if mice who displayed symptoms similar to a relapsing-remitting form of MS could experience fewer attacks after being treated with an injectable form of Del-1.
Results
The authors found that the amount of Del-1 in the CNS was significantly lower in mice with MS-like disease compared to healthy mice, suggesting that reduced Del-1 may be linked to MS. When Del-1 was experimentally switched off, both MS-like severity and inflammation were aggravated, with an increase in nerve injury, higher levels of IL-17, blood-brain barrier damage and unregulated immune cell infiltration into the CNS. These findings reveal that Del-1 normally protects against the damaging inflammation seen in an MS-like disease. To further test this hypothesis, researchers injected the MS-exhibiting mice with Del-1, which reduced the severity of disease symptoms.
Comment
Currently there is one other therapy available for MS (called Tysabri) that works to keep harmful immune cells out of the CNS, specifically by using antibodies to block the interaction between these immune cells and the blood-brain barrier. The results of this study add to that knowledge and recognize the inherent anti-inflammatory nature of Del-1, which acts as a “gatekeeper” that protects the CNS from infiltrating immune cells. The study further shows that a decline in the function of Del-1 may be a risk factor for MS, and that replacing Del-1 in mice that have an MS-like condition can curtail further relapses, thus sowing the seeds for a new therapeutic approach for treating people with MS in the future.
Source
Choi EY et al. Developmental endothelial locus-1 is a homeostatic factor in the central nervous system limiting neuroinflammation and demyelination. Mol Psychiatry. 2014 [Epub ahead of print]