Multiple sclerosis (MS) research has long focused on the immune system’s adaptive branch — the T cells and B cells that current disease-modifying therapies are built to suppress. A study published in Nature Neuroscience shifts attention to a different culprit: a fat-engorged population of brain immune cells called “foamy” microglia, which the researchers link directly to disease progression rather than just injury clean-up.
What are foamy microglia?
Microglia are the brain’s resident immune cells, normally tasked with clearing debris and pathogens. In and around MS lesions, some microglia and infiltrating macrophages become engorged with lipids as they attempt to clear myelin debris, taking on a swollen, “foamy” appearance under the microscope. These lipid-laden cells have been observed in MS tissue for years, but their exact role — bystander clean-up crew, or active driver of damage — has been unclear.
The study
The paper, “Foamy microglia link oxylipins to disease progression in multiple sclerosis” (Nature Neuroscience, vol. 29, pp. 1585–1598, published online May 2026), was led by researchers spanning three Dutch research centres: the Department of Molecular Physiology at the Leiden Institute of Chemistry, Leiden University; the Neuroimmunology Research Group at the Netherlands Institute for Neuroscience (NIN), home to the Netherlands Brain Bank; and the Biomolecular Mass Spectrometry and Proteomics group at Utrecht University’s Utrecht Institute for Pharmaceutical Sciences. Roche Innovation Center Basel also contributed to the work. Senior authors include Mario van der Stelt (Leiden, lipid chemical biology), Inge Huitinga (NIN, who directs the Netherlands Brain Bank), and Albert J. R. Heck (Utrecht, mass spectrometry).
Using donated post-mortem brain tissue from people who had secondary progressive MS — made available through the Netherlands Brain Bank — combined with lipidomic profiling, mass spectrometry and animal models of demyelination, the team characterised a specific population of GPNMB-positive foamy microglia and macrophages concentrated in progressive MS lesions.
What they found
- Disrupted lipid handling: foamy microglia/macrophages showed signs of lysosomal stress and disrupted lipid metabolism, alongside markers of heightened phagocytic activity.
- A distinct lesion chemistry: lesions enriched in foamy microglia also showed elevated oxylipins (lipid-derived signalling molecules), altered cholesterol handling, and increased B cell infiltration — a chemical signature tying the innate lipid response to the adaptive immune activity MS therapies already target.
- A druggable target: the enzyme monoacylglycerol lipase (MAGL), part of the pathway that processes these lipids, emerged as a candidate therapeutic target. Inhibiting MAGL promoted recovery in animal models of demyelination.
- A possible biomarker: oxylipin levels measured in cerebrospinal fluid correlated with the proportion of foamy lesions in the brain, raising the possibility of tracking disease progression through a spinal fluid sample rather than relying solely on imaging or post-mortem tissue.
Why it matters for MS research
Secondary progressive MS, where disability accumulates gradually rather than through discrete relapses, remains far harder to treat than relapsing-remitting disease. Most approved disease-modifying therapies act on T and B lymphocytes and do relatively little to slow progression once it sets in. By identifying a specific, lipid-driven microglial state as a progression driver — and a specific enzyme and biomarker candidate within that pathway — this study gives progressive MS research a more concrete mechanistic target than it has had before. As with any single study built on post-mortem tissue and animal models, translating the MAGL-inhibition finding into a human therapy, and validating the CSF oxylipin signature as a clinical biomarker, will require further work before either reaches patients.
A cross-institutional Dutch collaboration
The study is a case study in how brain banking, chemical biology and analytical chemistry infrastructure combine across institutions: the Netherlands Brain Bank at NIN supplied the human tissue that made lesion-level analysis possible, Leiden’s lipid chemistry groups characterised the metabolic pathway and MAGL target, and Utrecht’s mass spectrometry and proteomics group provided the molecular profiling that tied lipid changes to specific cell states — work that also involved industry collaborators at Roche. That combination of a national brain tissue resource with specialised chemistry and mass-spectrometry expertise across three institutions is a large part of why the lesion-level lipid signature could be resolved at all.
For research-administration audiences, this kind of multi-site, multi-domain collaboration — spanning a national biobank, two university chemistry departments and an industry partner — illustrates the coordination that translational and clinical research management increasingly has to support, from tissue-access agreements to shared data and authorship arrangements across institutions and sectors.
Source
van der Vliet, D., Di, X., Shamorkina, T.M., et al. “Foamy microglia link oxylipins to disease progression in multiple sclerosis.” Nature Neuroscience 29, 1585–1598 (2026). https://doi.org/10.1038/s41593-026-02302-3
