Microglia regulate myelin growth and integrity in the central nervous system

Myelin is required for the function of neuronal axons in the central nervous system, yet the mechanisms supporting myelin health are unclear. Although central nervous system macrophages have been implicated, it is unknown which macrophage populations are involved and which aspects of myelin health they influence. Here, we show that resident microglia are critical for the maintenance of myelin health in adulthood in both mouse and human. We demonstrate that whereas microglia are dispensable for developmental myelin ensheathment, they are required for subsequent regulation of myelin growth and associated cognitive function, and for the preservation of myelin integrity by preventing its degeneration. We discovered that loss of myelin health in the absence of microglia is underpinned by the appearance of a myelinating oligodendrocyte subpopulation with altered lipid metabolism, regulated by a disruption of the TGFß1-TGFßR1 axis. Our findings highlight microglia as promising therapeutic targets for conditions where myelin growth and integrity are dysregulated, such as in ageing and neurodegenerative disease. Overall design: FIRE?/? and wildtype female mice at 1 month of age. The olfactory bulbs and cerebellum were removed. Hippocampi from both hemispheres and the remainder of the left hemisphere (without the hippocampus) were used for the single cell RNA sequencing.