Contribution of 25-hydroxycholesterol to the cross-interaction of the immune and nervous systems

Abstract

25-hydroxycholesterol (25HC) is produced from cholesterol by cholesterol-25-hydroxylase, and its expression, similar to the 25HC level, increases significantly in macrophages, dendritic cells, and microglia during an inflammatory reaction. In turn, 25HC acts on many immune cells; therefore, it can modulate the course of the inflammatory reaction and prevent the penetration of viruses into cells. Data are accumulating about the involvement of 25HC in the regulation of synaptic transmission in both the central and peripheral nervous systems. 25HC production is increased not only during inflammation but in certain neurodegenerative diseases, such as Alzheimer’s disease and amyotrophic lateral sclerosis; thus, this hydroxycholesterol can be important in the adaptation of synaptic activity to inflammatory conditions, pathogenesis of neurodegenerative diseases, and formation of synaptic dysfunctions. The targets of 25HC in the nervous system are glutamate NMDA receptors, liver X-receptors, and estrogen receptors. 25HC can also directly influence the properties of synaptic membranes by changing the formation of membrane microdomains (lipid rafts) where proteins, which are important for synaptic plasticity, are clustered. Current data indicate that the effects of 25HC strongly depend on its concentration and “context” (norm, pathology, and presence of an inflammatory reaction) in which the effect of 25HC is being investigated. This minireview focused on the key aspects of the action of 25HC as both a local regulator of cholesterol homeostasis and a paracrine molecule that realizes the influence of inflammation on neurotransmission processes in the central and peripheral nervous systems.