Aged lipid‐laden microglia display impaired responses to stroke

• Published in: EMBO molecular medicine Vol. 15; no. 2; pp. e17175 - n/a
• Main Authors: Arbaizar‐Rovirosa, Maria, Pedragosa, Jordi, Lozano, Juan J, Casal, Carme, Pol, Albert, Gallizioli, Mattia, Planas, Anna M
• Format: Journal Article
• Language: English
• Published: England EMBO Press 08.02.2023; John Wiley and Sons Inc; Springer Nature
• Subjects: Aging; Animals; brain; Brain Ischemia - metabolism; Colony-stimulating factor; Gene expression; Immune response; immunometabolism; Inflammation; Innate immunity; Ischemia; Ischemia - metabolism; lipid droplets; Lipid metabolism; Lipids; Lipids - pharmacology; Macrophage colony-stimulating factor; Mice; Mice, Inbred C57BL; Microglia; Microglia - metabolism; Microglial cells; Microscopy; Ontology; Proteins; Recovery of function; Reperfusion; Stroke; Stroke - metabolism; Traumatic brain injury; brain; lipid droplets; immunometabolism; microglia; ischemia
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.202217175

Microglial cells of the aged brain manifest signs of dysfunction that could contribute to the worse neurological outcome of stroke in the elderly. Treatment with colony‐stimulating factor 1 receptor antagonists enables transient microglia depletion that is followed by microglia repopulation after treatment interruption, causing no known harm to mice. We tested whether this strategy restored microglia function and ameliorated stroke outcome in old mice. Cerebral ischemia/reperfusion induced innate immune responses in microglia highlighted by type I interferon and metabolic changes involving lipid droplet biogenesis. Old microglia accumulated lipids under steady state and displayed exacerbated innate immune responses to stroke. Microglia repopulation in old mice reduced lipid‐laden microglia, and the cells exhibited reduced inflammatory responses to ischemia. Moreover, old mice with renewed microglia showed improved motor function 2 weeks after stroke. We conclude that lipid deposits in aged microglia impair the cellular responses to ischemia and worsen functional recovery in old mice. Synopsis Stroke outcome is impaired in old subjects. Here, microglia of aged mice are shown to accumulate lipids and display exacerbated inflammation after stroke. The microglia lipid droplet content was reduced by microglia depletion/repopulation in old mice, and motor function was improved after stroke. Ischemic stroke induced acute lipid droplet biogenesis in microglia. Aging caused lipid droplet accumulation in microglia and changes in lipid pathways under a steady state. Old mice showed worse outcomes after stroke, and their microglia displayed exaggerated innate immune reactions. Renewal of microglia in old mice by transient treatment with a CSF1R inhibitor reduced lipid droplets. Renewed microglia of old mice showed less inflammation after stroke, and motor function was improved. Stroke outcome is impaired in old subjects. Here, microglia of aged mice are shown to accumulate lipids and display exacerbated inflammation after stroke. The microglia lipid droplet content was reduced by microglia depletion/repopulation in old mice, and motor function was improved after stroke.