Heterogeneity of microglia and their differential roles in white matter pathology

Abstract

Microglia are resident immune cells that play multiple roles in central nervous system (CNS) development and disease. Although the classical concept of microglia/macrophage activation is based on a biphasic beneficial-versus-deleterious polarization, growing evidence now suggests a much more heterogenous profile of microglial activation that underlie their complex roles in the CNS. To date, the majority of data are focused on microglia in gray matter. However, demyelination is a prominent pathologic finding in a wide range of diseases including multiple sclerosis, Alzheimer's disease, and vascular cognitive impairment and dementia. In this mini-review, we discuss newly discovered functional subsets of microglia that contribute to white matter response in CNS disease onset and progression. Microglia show different molecular patterns and morphologies depending on disease type and brain region, especially in white matter. Moreover, in later stages of disease, microglia demonstrate unconventional immuno-regulatory activities such as increased phagocytosis of myelin debris and secretion of trophic factors that stimulate oligodendrocyte lineage cells to facilitate remyelination and disease resolution. Further investigations of these multiple microglia subsets may lead to novel therapeutic approaches to treat white matter pathology in CNS injury and disease.

Keywords: demyelination; microglia; oligodendrocyte; white matter damage; white matter repair.

Figure 1

Effects of microglia‐derived factors on oligodendrocyte lineage depending on microglial subsets. A pro‐inflammatory microglial subset secretes cytokines and reactive oxygen species (ROS) that can directly damage oligodendrocytes thus resulting in demyelination. Immuno‐regulatory subsets secrete trophic factors that promote OPC migration and differentiation thus resulting in remyelination. Switching the pro‐inflammatory subset into an immuno‐regulatory subset may represent a potential therapeutic approach for rescuing white matter in CNS injury and disease. Note that microglia‐derived TNFα and IL‐1β can both be cytotoxic or beneficial to oligodendrocyte lineage cells (marked in red). These complex effects are likely to be dependent on signals from neighboring cells and surrounding environmental conditions. Future studies are warranted to investigate how and why identical factors from microglia can show opposite effects on oligodendrocyte damage/recovery