Cholesterol metabolisms as key regulator of phagocyte function during remyelination Mikael Simons Institute of Neuronal Cell Biology, Technical University Munich, 80805 Munich, Germany German Center for Neurodegenerative Disease (DZNE), Munich, Germany
Age-associated decline in regeneration capacity limits the restoration of nervous system functionality in demyelinating diseases such as multiple sclerosis (MS). Yet, the factors responsible for this decline remain only partially understood. Úsing a toxin-induced demyelination model, we found that aged mice fail to resolve the inflammatory response that is induced after myelin injury. Phagocytes accumulated excessive amounts of myelin debris, which triggered cholesterol crystal formation, phagolysosomal membrane rupture and inflammasome stimulation. We found that apolipoprotein E prevented myelin debris and cholesterol overload. Remarkably, stimulation of reverse cholesterol transport by nuclear liver X receptor agonist treatment was sufficient to restore the capacity of old mice to regenerate lesioned tissue. We conclude that in demyelinating lesions, cholesterol-rich myelin debris can overwhelm the efflux capacity of phagocytes, resulting in a phase transition of free cholesterol into crystals thereby inducing a maladaptive immune response that impedes tissue regeneration.
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