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Lipid Metabolism impacts Remyelination

Research Article Remyelination requires orchestrated lipid droplets formation and cholesterol esterification by microglia.

About the authors


Olga (Olya) Vvedenskaya and
Henri M Deda
Olga (Olya) Vvedenskaya
Sci. Communications Officer

Dr. Dr. Olya Vvedenskaya studied medicine, and further obtained her PhD in the field of molecular oncology. She loves to deliver scientific messages in a clear and accessible manner.


Henri M Deda
Communications Officer

Henri Deda holds a degree in Molecular Bioengineering. He is spirited to discover what scientists are interested in and to provide concise answers.

Resources


TREM2-dependent lipid droplet biogenesis…

Gouna et al. | JEM (2021)


Mouse lipidomics reveals inherent flexibility…

Surma et al. | SciRep (2021)


Systematic screening for novel lipids by…

Papan et al. | Anal. Chem. (2014)


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Summary

• Remyelination requires myelin debris clearance
• Microglia phagocytic function relies on lipid droplet genesis
• TREM2 receptor is essential for lipid droplet formation and thus the protective response required for remyelination

Authors
Olga (Olya) Vvedenskaya and
Henri M Deda

REMYELINATION is a regenerative process that can occur during central nervous system (CNS) damage. In cases like multiple sclerosis or Alzheimer’s disease, remyelination often fails during the progressive phase of a disease.

An infographic showing a neuron and its dendrites, synapses, and highlighting the organization of myelin, including nodes of Ranvier, Schwann cells, myelin sheaths, and neurofibrils.

Microglia – a type of glial cells – are innate immune cells of the brain and spinal cord, that are an essential player in inflammation response and in myelin repair after the demyelinating injury.

It is essential to understand the details of remyelination and lipid composition remodeling in order to work on the interventions of myelin sheath reconstruction.

In case of CNS injury, myelin debris is generated from the myelin sheath covering an axon. The debris consists of myelin membrane fragments, cell fragments, and certain lipids, such as cholesterol, phospholipids, ceramides, and further sphingolipids.

An infographic depicting the lipid content of damaged myelin: sphingolipids, ceramides, cholesterol, phospholipids, and myelin debris.

Under normal conditions, during the clearance of myelin debris the cholesterol (unlike other lipids) cannot be degraded by the lysosomal enzymes and is transferred from late endosomes to endoplasmic reticulum (ER). ER, on its turn, cannot cope with the excessive amount of free cholesterol, that is why free cholesterol is being esterified into cholesteryl esters and stored in lipid droplets.

Cholesterol exposure is required in microglia macrophages for a proper myelin debris uptake. When this buffering mechanism of lipid droplet formation is defective, microglia phagocytes do not resolve from demyelinating lesions, and the regenerative response during remyelination fails.

Gouna and Simons studied the role of triggering receptor expressed on myeloid cells 2 (TREM2) in the metabolic pathway required for remyelination, in particular, for myelin debris clearance in cell culture and mice brain and spinal tissue. This study shows that in case of TREM2 deficiency the adaptive response to excess cholesterol exposure is compromised. The reason could be that TREM2-dependent gene expression is necessary to trigger the generation of enzymes required for lipid droplet formation and thus for proper remyelination.

Quantification of the number of lipid droplets per cell in postnatal microglia. *, P < 0.05; **, P < 0.01; ***, P < 0.001.

Comparison of lipid droplet formation in TREM2-KO and WT cells: Quantification of the number of lipid droplets per cell in postnatal microglia. *, P < 0.05; **, P < 0.01; ***, P < 0.001.
Gouna et al., Journal of Experimental Medicine (2021), doi:10.1084/jem.20210227

The lipidomic analysis reveals that TREM2-deficient phagocytes not only fail to generate cholesterol esters but also are deficient in triacylglycerol (TAG) generation. The accumulation of phosphatidic acid in TREM2-deficient phagocytes points to decreased activity of lipin phosphatidic acid phosphatase, which catalyzes the conversion of phosphatidic acid to diacylglycerol. Lipin is unique among biosynthetic enzymes in TAG generation as its enzyme activity is regulated by its transition between the ER and the cytosol.

A Untargeted lipidomics analysis of WT and TREM2 KO cells cultured in serum-free media or with myelin for 8 or 24 h. B and C Analysis of ER stress by quantification of phosphorylated eIF2α (B) and phosphorylated JNK (C), measured by Western blot. **, P < 0.01; ***, P < 0.001.

Comparison of lipid profiles in TREM2-KO and WT cells and ER stress presence: A Untargeted lipidomics analysis of WT and TREM2 KO cells cultured in serum-free media or with myelin for 8 or 24 h. B and C Analysis of ER stress by quantification of phosphorylated eIF2α (B) and phosphorylated JNK (C), measured by Western blot. **, P < 0.01; ***, P < 0.001.
Gouna et al., Journal of Experimental Medicine (2021), doi:10.1084/jem.20210227

Because TREM2-deficient phagocytes are able to internalize myelin debris but fail to mount the necessary for proper remyelination 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, and the authors observed evidence of ER stress in myelin debris–loaded TREM2-deficient phagocytes. Previously, an ER stress has been demonstrated to impact the vaccine adjuvant AS03 but is also investigated as a novel therapeutic approach for triple negative breast cancer.

An infographic visualizing TREM2 WT and TREM2 knockout microglia dealing with cholesterol from the myelin debris following myelin injury. TREM2 knockout microglia cells cannot process cholesterol which causes ER stress in these microglia.

This study investigates the phagocytes function of clearing cholesterol excess that occurs as a result of a demyelinating injury. In summary, cholesterol efflux and esterification are essential to promote the resolution of innate immune inflammation and to support remyelination.

Lipotype Lipidomics technology can be used to characterize the lipid profile of primary patient samples, tissue from model organisms, and in vitro samples. These data can provide insight on a wide variety of diseases, including neurodegeneration, cancers, cardiovascular diseases, and metabolic disorders.

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