Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system, in which the body’s own immune cells attack the fatty, insulating myelin sheath surrounding nerve fibers. The regeneration of intact myelin sheaths is a necessary prerequisite for patients to recover from MS relapses. Nevertheless, the body’s ability to regenerate myelin decreases with age.
A team led by Prof. Mikael Simons from the Technical University of Munich (TUM) has now published a possible explanation in the journal Science: Fat derived from myelin, which is not carried away rapidly enough by phagocytes can trigger chronic inflammation that in turn impedes regeneration. Furthermore, in a second publication Simons’ team describes the discovery of novel cell type, which appears only when a myelin sheath is being created.
The myelin sheath plays a decisive role in the function of the central nervous system: it is a specialized membrane enriched in lipids, which insulates nerve fibers so that electrical signals can be passed on quickly and efficiently. In MS, there is a multifocal autoimmune attack against the myelin sheath in the central nervous system, which causes neurological deficits such as loss of motor function. Regeneration of myelin is possible, but in MS it is inadequate.
One of the reasons is presumably chronic inflammation occurring in the lesions. A team led by TUM Molecular Neurobiology professor Mikael Simons has now discovered that after the destruction of myelin crystalline cholesterol can trigger persistent inflammation which prevents regeneration, similar as in arteriosclerosis.
Dangerous crystals
“Myelin contains a very high amount of cholesterol,” explains Prof. Simons. “When myelin is destroyed, the cholesterol released has to be removed from the tissue.” This is performed by microglia and macrophages, also referred to as phagocytes. They take up the damaged myelin, digest it and transport the non-digestible remainder, such as cholesterol, out of the cell by transport molecules. However, if too much cholesterol accumulates in the cell, cholesterol can forms needle-shaped crystals, which cause damage the cell. Using a mouse model, Simons and his team showed the devastating impact of the crystalline cholesterol: It activates the so-called inflammasome in phagocytes, which results in the release of inflammatory mediators, attracting even more immune cells. “Very similar problems occur in arteriosclerosis, however not in the brain tissue, but in blood vessels,” says Simons.
How well the microglia and macrophages did their job was ultimately also dependent on the age of the animal: the older the animal, the less effective was the clearance of cholesterol and the stronger the chronic inflammations. “When we treated the animals with a medication that facilitates the transport of cholesterol out of the cells, inflammation decreased and myelin was regenerated,” says Mikael Simons. Next he and his team want to investigate whether this mechanism can be used therapeutically to promote regeneration in MS.
