Analysis of microglial gene expression: identifying targets for CNS neurodegenerative and autoimmune disease.

Abstract

Microglia are the tissue macrophage of the central nervous system (CNS) and their activation is among the earliest signs of CNS dysfunction and disease. Because microglia express many macrophage markers, they are presumed to act primarily as effectors of CNS inflammation and destruction. While such responses are beneficial to the extent that they destroy CNS pathogens, these responses do have the potential to have neurotoxic outcomes. Consequently, therapies for many CNS neurodegenerative and inflammatory diseases have been directed at suppressing microglial function. There is evidence to suggest that microglia play an important role during CNS development and maintenance of CNS function that may go beyond simple defense against pathogens. Molecular analysis of microglial phenotypes and function has revealed three striking findings: (i) that microglia are a unique CNS-specific type of tissue macrophage; (ii) that they are highly heterogeneous within the healthy CNS; and (iii) that microglial responses are exquisitely tailored to specific regions of the CNS and specific pathological insults. We suggest that ubiquitous suppression (rather than targeted manipulation) of microglial function may fail to fully ameliorate CNS pathology and may even ultimately promote maladaptive outcomes.