Microglia are an essential player in myelin repair after the demyelinating injury due to their myelin debris clearance function. During the process of demyelination, the lipid-rich myelin debris with high cholesterol content is generated.

In the process of debris clearance cholesterol cannot be degraded by the lysosomal enzymes and is transferred from late endosomes to the endoplasmic reticulum (ER). ER in its turn cannot cope with the excessive amount of free cholesterol therefore cholesterol is being esterified and stored in lipid droplets. When this buffering mechanism is defective, phagocytes do not resolve from demyelinating lesions, and the regenerative response fails.

Gouna and Simons studied the role of triggering receptors expressed on myeloid cells 2 (TREM2) in this process. They observed, that in the case of TREM2 deficiency the adaptive response to excess cholesterol exposure is compromised. It appears that TREM2-dependent gene expression is necessary to trigger the generation of enzymes required for lipid droplet formation. Because TREM2-deficient phagocytes are able to internalize myelin debris but fail to mount the necessary metabolic responses to the internalized cargo, they become exposed to the toxicity of free cholesterol that builds up with time.

Consequently, cholesterol-induced cellular stress develops in myelin debris–loaded TREM2-deficient phagocytes.

The authors perform a full lipidome analysis of the TREM2-deficient phagocytes and discover that these cells not only fail to generate cholesterol esters but also are deficient in TAG generation.

Discover more here: https://www.lipotype.com/lipidomics-resource-center/?q=phagocytes%20is%20required

#lipidome #myelin #remyelination #microglia #LipidDroplet