Microglia at the scene of the crime: what their transcriptomics reveal about brain health

Abstract

Purpose of reviewMicroglia, which arise from primitive myeloid precursors that enter the central nervous system (CNS) during early development, are the first responders to any perturbance of homeostasis. Although their activation has become synonymous with neurologic disease, it remains unclear whether microglial responses are the cause of or response to neuropathology. Here, we review new insights in the roles of microglia during CNS health and disease, including preclinical studies that transcriptionally profile microglia to define their functional states.Recent findingsConverging evidence suggests that innate immune activation of microglia is associated with overlapping alterations in their gene expression profiles regardless of the trigger. Thus, recent studies examining neuroprotective microglial responses during infections and aging mirror those observed during chronic neurologic diseases, including neurodegeneration and stroke. Many of these insights derive from studies of microglial transcriptomes and function in preclinical models, some of which have been validated in human samples. During immune activation, microglia dismantle their homeostatic functions and transition into subsets capable of antigen presentation, phagocytosis of debris, and management of lipid homeostasis. These subsets can be identified during both normal and aberrant microglial responses, the latter of which may persist long-term. The loss of neuroprotective microglia, which maintain a variety of essential CNS functions, may therefore, in part, underlie the development of neurodegenerative diseases.SummaryMicroglia exhibit a high level of plasticity, transforming into numerous subsets as they respond to innate immune triggers. Chronic loss of microglial homeostatic functions may underlie the development of diseases with pathological forgetting.

Senolytic treatment depletes microglia and decreases severity of experimental autoimmune encephalomyelitis

“…While there is a consensus that microglia occupy a continuum of states and functions dependent on their intrinsic gene and protein expression, and cues from their local microenvironment, equally there is significant evidence for certain genes consistently dysregulated in microglia across numerous different diseases and in aging 6,10 . It is important to note that many studies on human microglia are often limited by the amount and quality of microglial nuclei, and systematic analysis of microglial gene expression changes compared to mouse gene expression changes in aging and disease finds that microglial signatures comparing across mice and human are not highly similar 2,36 .…”

“…The continuum of microglial states from homeostatic to injurious exists upon the axes of healthy to injured and young to old 10 . As a dividing cell population, microglia are susceptible to cellular senescence, and senescent microglia can perpetuate CNS inflammation and injury 11 .…”

West Nile Virus-Induced Expression of Senescent Gene Lgals3bp Regulates Microglial Phenotype within Cerebral Cortex

“…This comparison revealed broad similarities in gene expression between WNV-activated and aged microglia (Table 1). Of note, expression of genes defining homeostatic microglia remain mostly unchanged during aging, while many of these genes are down-regulated during viral infection [23,24]. To build on these initial findings, we performed a bulk RNA-sequencing analysis of CD11b+ cells isolated from the forebrains of WNV-infected 16-or 85-week-old animals at 30 DPI.…”

Bone Marrow: The Central Immune System

“…Each cell is constantly surveilling its microenvironment, screening for pathogens, but also removing cell debris and metabolites, grooming neighboring cells, and facilitating cellular crosstalk [100]. This "tissue surveillance" by microglia is an essential process for CNS homeostasis and development [101]. Microglia continuously monitor and sculpt synapses, allowing for the remodeling of brain circuits [102].…”