Microglia regulate myelin growth and integrity in the central nervous system white matter
Disruption of myelin structure occurs with ageing and neurodegenerative disease, and involves myelin which is outfolding, unravelling, less compact, and thicker. This is associated with nerve dysfunction and cognitive decline; however, the mechanisms underpinning appropriate myelin structure, i.e. myelin integrity, are unclear. The central nervous system (CNS)-resident macrophages microglia are prime candidates, as they are considered to instruct maturation of the myelinproducing oligodendrocytes and thus, myelin formation in development and following demyelination, based on studies of microglial depletion following loss-of-function of the pro-survival colony stimulating factor 1 receptor (CSF1R). As this approach also targets other CNS macrophages which may contribute to these processes, I sought to investigate the specific roles of microglia in regulating myelin health. To achieve this, I utilised a recently developed transgenic mouse model, in which deletion of the FIRE super-enhancer of the Csf1r gene (FIREΔ/Δ) leads to an absence of microglia, while other CNS macrophages are present. FIREΔ/Δ mice had no impairment in oligodendrocyte maturation or myelin formation in the white matter, yet showed a loss of its integrity, with impaired compaction, increased thickness and outfoldings and unravelling of myelin, culminating in demyelination. Results were recapitulated by depleting microglia in adulthood, indicating a role for microglia in myelin maintenance rather than development. These myelin changes were associated with impaired cognitive flexibility. Loss of myelin integrity was also observed in a human condition (ALSP) where CSF1R mutations result in reduced white matter microglia and dementia. To identify the mechanism by which microglia regulate myelin integrity, singlecell RNA sequencing of FIREΔ/Δ mice was performed, which revealed a new oligodendrocyte subpopulation. The genes upregulated in this oligodendrocyte population were predicted to be regulated by transforming growth factor β 1 (TGFβ1), a factor primarily produced by microglia, which regulates expression ii of its receptors e.g., TGFβR1. Accordingly, TGFβ1 levels in FIREΔ/Δ white matter were reduced, and oligodendroglial TGFβR1 expression was downregulated. Additionally, the conditional knockout of Tgfbr1 in mature oligodendrocytes was sufficient to cause a loss of myelin integrity, mirroring the results in the FIREΔ/Δ mice. Reinstating TGFβ downstream signalling via administration of a small molecule agonist (SRI-011381) rescued the loss of myelin integrity in FIREΔ/Δ mice, significantly reducing inner tongue enlargement and myelin thickness versus vehicle-treated mice such that these were comparable to wildtype controls. My findings reveal that microglia regulate myelin health at later stages than previously thought, preserving the structural integrity of myelin rather than driving initial myelin formation. These findings have important implications for understanding the pathological mechanisms underpinning loss of myelin integrity in ageing and neurodegenerative diseases, where dysregulated microglia may represent key therapeutic targets to restore CNS health.
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