179 White matter microglia heterogeneity Introduction Microglia, the resident macrophages in the central nervous system (CNS), were discovered over 100 years ago by Pío del Río-Hortega, and have since been the focus of many studies. While historically microglia have been described as the phagocytes of the CNS, advancements in research techniques over the last few decades have shown that microglia have diverse roles (Fig. 1). Their main functions are to protect the CNS parenchyma by constantly scanning their surroundings for potential harm1 and to regulate CNS homeostasis2. Microglia comprise roughly 10% of the total glial population, but unlike astrocytes or oligodendrocytes, microglia are derived from yolk sac progenitors that populate the CNS during embryonic development3. Throughout life, microglia have the ability to self-renew through proliferation, while during disease this process shifts towards clonal expansiondepending on the local need formicroglia4. Such proliferation of microglia is associated with apoptosis that removes excess numbers of microglia to keep the cell numbers in check5. This self-renewal capacity indicates that microglia are subject to constant changes independent of disease or homeostatic activities. Following injury, microglia undergo morphological and transcriptional changes to adapt their behaviour in response to the type of injury. The versatile nature of microglia also proves to be one of major the challenges in microglia research – ex vivo culturing of microglia leads to fast and extensive downregulation of microglia-specific genes and upregulation of genes associated with acute inflammatory responses and immune functions6, making it difficult to decipher their roles solely using in vitro approaches. While microglia are often considered as drivers of CNS pathology (Fig. 2), leukodystrophies and myelin damage are associated with loss of microglial functions and decrease in microglial numbers7. Microglia are thus essential for normal functioning of the CNS white matter. Additionally, white matter integrity is essential for cognitive, sensory, and motor functions, throughout the lifespan ranging from development to ageing8-12. Aberrations in myelin structure are observed in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), and viral encephalitis. These findings indicate a strong link between white matter integrity and neuronal health and function. As white matter is increasingly implicated in a range of CNS functions, the need to elucidate the roles of microglia within the white matter, and their heterogeneous functions in health and disease, is critical. Here, we review the current knowledge of microglia heterogeneity in the white matter during development and ageing, and their roles in white matter diseases and neurodegenerative diseases in which white matter is affected. Finally, we discuss potential therapeutic avenues for microglial targeting in these diseases. Microglia heterogeneity in the CNS Historically, microglia have been compared to peripheral blood derived macrophages, and consequently, classifications used to describe macrophage activation states in non-CNS tissue were applied to microglia. Initially, microglia were categorised as ‘resting’ under homeostatic conditions, M1 under pro-inflammatory conditions (‘classically activated’) or M2 under anti-inflammatory conditions (‘alternatively activated’)13,14. However, in vivo, microglia adopt intermediate phenotypes expressing both pro-inflammatory and anti-inflammatory markers15,16, suggesting a more complex profile. Additionally, it is unclear as to whether M1 or M2 microglia states exist in vivo17. Proteomics and single cell/nucleus RNA-seq analyses have supported the concept that microglia heterogeneity is far more diverse, and that this heterogeneity is influenced by regional differences in the CNS, age, and the type of injury.
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