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Updated: May 23, 2026
Comprehensive Autopsy Program for Individuals with Multiple Sclerosis
Published on: July 19, 2019
Foamy microglia link oxylipins to disease progression in multiple sclerosis
Daan van der Vliet1,2, Xinyu Di1, Tatiana M Shamorkina3,4
1Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, the Netherlands.
Abstract:
Multiple sclerosis (MS) is a chronic neuroinflammatory disease in which demyelinating white matter lesions accumulate and expand, driving irreversible disability. Here we identify a distinct population of foamy GPNMB+ microglia/macrophages associated with lesion expansion in secondary progressive MS. Using integrated lipidomic, transcriptomic, proteomic, chemical proteomic and histological analyses of human postmortem MS lesions, we show that lesions containing foamy microglia/macrophages exhibit disrupted lipid metabolism, lysosomal stress and markers associated with heightened phagocytosis and antigen presentation without classical pro-inflammatory signatures. These lesions are enriched for oxylipins, bismonoacylglycerolphosphates and cholesterol esters, and are associated with increased B cell infiltration and IgG1. Monoacylglycerol lipase (MAGL), a lipid-metabolizing enzyme enriched in lesions with foamy microglia/macrophages, emerged as a potential therapeutic target. Inhibition of MAGL promoted lesion recovery and reduced microgliosis in a mouse model of demyelination. Finally, oxylipins in cerebrospinal fluid correlate with the proportion of foamy lesions, suggesting potential biomarkers for progression. Our findings implicate disturbed lipid metabolism in chronic MS pathology and suggest that foamy microglia/macrophages are an interesting cell type to target for progressive disease.
Insights
Researchers discovered foamy GPNMB+ microglia/macrophages in progressive multiple sclerosis (MS) lesions. Targeting monoacylglycerol lipase (MAGL) in these lesions may offer a new therapeutic strategy for MS.
Area of Science:
- Neuroimmunology
- Neurobiology
- Lipidomics
Background:
- Multiple sclerosis (MS) is a chronic neuroinflammatory disease characterized by demyelination and progressive disability.
- Lesion expansion in MS is driven by complex cellular and molecular processes.
- Understanding the specific cell types and metabolic changes within MS lesions is crucial for developing effective treatments.
Purpose of the Study:
- To identify and characterize distinct cell populations within expanding MS lesions.
- To investigate the role of lipid metabolism in the pathology of progressive MS.
- To explore potential therapeutic targets for mitigating MS progression.
Main Methods:
- Integrated analyses of human postmortem MS lesions including lipidomics, transcriptomics, proteomics, chemical proteomics, and histology.
- Identification and characterization of foamy GPNMB+ microglia/macrophages.
- Inhibition of monoacylglycerol lipase (MAGL) in a mouse model of demyelination.
- Analysis of cerebrospinal fluid (CSF) for potential biomarkers.
Main Results:
- A distinct population of foamy GPNMB+ microglia/macrophages was identified in expanding MS lesions.
- These lesions exhibit disrupted lipid metabolism, lysosomal stress, and heightened phagocytosis/antigen presentation without classical pro-inflammatory signatures.
- Lesions were enriched for oxylipins, bismonoacylglycerolphosphates, and cholesterol esters, with increased B cell infiltration and IgG1.
- Monoacylglycerol lipase (MAGL) was identified as a key enzyme in these lesions.
- MAGL inhibition promoted lesion recovery and reduced microgliosis in a mouse model.
- CSF oxylipins correlated with foamy lesion proportion, suggesting potential biomarkers.
Conclusions:
- Disturbed lipid metabolism contributes to chronic MS pathology.
- Foamy GPNMB+ microglia/macrophages are a significant cell type in progressive MS lesions.
- Targeting MAGL represents a promising therapeutic strategy for progressive MS.
- CSF oxylipins may serve as biomarkers for MS progression.
