Microglial heterogeneity: distinct cell types or differential functional adaptation?

Abstract

Microglia were first characterized by del Rio Hortega about 100 years ago but our understanding of these cells has only gained traction in the last 20 years. We now recognize that microglia are involved in a plethora of activities including circuitry refinement, neuronal and glial trophic support, cell number modulation, angiogenesis and immune surveillance. Specific to immune surveillance, microglia detect threats which then drive their transformation from ramified to amoeboid cells. This morphological transition is accompanied by changes in cytokine and chemokine expression, which are far less conserved than morphology. To simplify discussion of these expression changes, nomenclature ascribed to states of macrophage activation, known as Macrophage 1 (“M1”; classic) and Macrophage 2 (“M2”; alternative), have been assigned to microglia. However, such a classification for microglia is an oversimplification that fails to accurately represent the array of cellular phenotypes. Additionally, multiple subclasses of microglia have now been described that do not belong to the “M1/M2” classification. Here, we provide a brief review outlining the prominent subclasses of microglia that have been described recently. Additionally, we present novel NanoString data demonstrating distinct microglial phenotypes from three commonly used central nervous system inflammation murine models to study microglial response and conclude with an introduction of recent RNA sequencing studies. In turn, this may not only facilitate a more appropriate naming scheme for these enigmatic cells, but more importantly, provide a framework for generating microglial expression “fingerprints” that may assist in the development of novel therapies by targeting disease-specific microglial subtypes.