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.
Highlights
White matter primarily comprises myelinated axons that connect neurons in various regions of the brain
Damage or abnormalities in white matter can result in various neuronal diseases, such as multiple sclerosis (MS),[7-9] Alzheimer's disease (AD),[10-12] traumatic brain injury (TBI)[13-15] and vascular cognitive impairment and dementia (VCID) including subcortical ischemic vascular dementia (SIVD).[12,16,17]
TNFα and IL‐1β, mentioned earlier as oligodendrocyte‐damaging factors secreted by microglia, were found to play beneficial roles in remyelination as well along with other pro‐inflammatory factors such as CXCL13 and endothelin‐2.91-93 These contrasting effects were driven by time‐ dependent expression change of their different receptor subtypes or their promotion of secondary proremyelinating factor secretion in the later phase of disease onset, demonstrating complex roles of microglia in regulating the fate of oligodendrocyte lineage cells
Summary
White matter primarily comprises myelinated axons that connect neurons in various regions of the brain.
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