TREM2-dependent lipid droplet biogenesis in phagocytes is required for remyelination

Area of Science:

• Neuroimmunology
• Cellular Metabolism
• Myelin Biology

Background:

• Microglia play a crucial role in myelin repair following demyelinating injuries.
• The metabolic adaptations enabling microglia to clear myelin debris are not well understood.
• Cholesterol metabolism in microglia is critical for effective remyelination.

Purpose of the Study:

• To investigate the metabolic pathways, specifically cholesterol esterification and lipid droplet formation, in microglia during myelin debris clearance.
• To determine the role of the triggering receptor expressed on myeloid cells 2 (TREM2) in microglial metabolic adaptation and remyelination.
• To elucidate the link between endoplasmic reticulum (ER) stress and the failure of myelin repair in TREM2-deficient models.

Main Methods:

• Analysis of cholesterol esterification and lipid droplet biogenesis in male mouse microglia/macrophages after demyelinating injury.
• Assessment of microglial response and myelin debris clearance in wild-type and TREM2-deficient mice.
• Investigation of endoplasmic reticulum (ER) stress markers and their impact on lipid droplet formation.
• Intervention to alleviate ER stress in TREM2-deficient mice to observe effects on immune cell resolution and remyelination.

Main Results:

• Cholesterol esterification and lipid droplet generation are essential adaptive responses in microglia for myelin debris uptake and remyelination.
• Defective lipid droplet biogenesis leads to unresolved innate immune responses and failure of myelin repair.
• TREM2-deficient mice exhibit impaired adaptation to cholesterol, reduced lipid droplet formation, and increased ER stress upon demyelination.
• Alleviating ER stress in TREM2-deficient mice rescues lipid droplet formation and resolves the innate immune response, promoting myelin repair.

Conclusions:

• TREM2-dependent lipid droplet formation is a critical protective mechanism for microglia to manage cholesterol overload during demyelinating injury.
• The metabolic adaptation of microglia, particularly lipid droplet biogenesis, is essential for successful remyelination.
• TREM2 signaling pathway is vital for preventing ER stress and resolving the innate immune response, thereby facilitating myelin repair.