biostudies-literatureLoix MFonds Wetenschappelijk Onderzoek515https://www.ebi.ac.uk/biostudies/studies/S-EPMC11803036biostudies-literatureUnknown79(10)Foamy macrophages and microglia containing lipid droplets (LDs) are a pathological hallmark of demyelinating disorders affecting the central nervous system (CNS). We and others showed that excessive accumulation of intracellular lipids drives these phagocytes towards a more inflammatory phenotype, thereby limiting CNS repair. To date, however, the mechanisms underlying LD biogenesis and breakdown in lipid-engorged phagocytes in the CNS, as well as their impact on foamy phagocyte biology and lesion progression, remain poorly understood. Here, we provide evidence that LD-associated protein perilipin-2 (PLIN2) controls LD metabolism in myelin-containing phagocytes. We show that PLIN2 protects LDs from lipolysis-mediated degradation, thereby impairing intracellular processing of myelin-derivedCellular and molecular life sciences : CMLSPerilipin-2 limits remyelination by preventing lipid droplet degradation.PMC118030361141920N1S15519NWouters EBogie JFJLoix MSwinnen JVDehairs JMcManaman JLHendriks JJAVanherle SHaidar MKemps HfalsePerilipin-2 limits remyelination by preventing lipid droplet degradation.Foamy macrophages and microglia containing lipid droplets (LDs) are a pathological hallmark of demyelinating disorders affecting the central nervous system (CNS). We and others showed that excessive accumulation of intracellular lipids drives these phagocytes towards a more inflammatory phenotype, thereby limiting CNS repair. To date, however, the mechanisms underlying LD biogenesis and breakdown in lipid-engorged phagocytes in the CNS, as well as their impact on foamy phagocyte biology and lesion progression, remain poorly understood. Here, we provide evidence that LD-associated protein perilipin-2 (PLIN2) controls LD metabolism in myelin-containing phagocytes. We show that PLIN2 protects LDs from lipolysis-mediated degradation, thereby impairing intracellular processing of myelin-derived2022-01-01T00:00:00Z2022 Sep2025-04-04T01:36:19.732Z2025-04-04T01:36:19.732ZS-EPMC118030363610076410.1007/s00018-022-04547-0