Editors' ChoiceNeuroimmunology

Microglial Progenitors Lie in Wait

Sci. Signal.  22 Apr 2014:
Vol. 7, Issue 322, pp. ec108
DOI: 10.1126/scisignal.2005391

Microglia are innate immune cells that reside in the brain and are derived from hematopoietic cells in the yolk that migrate into the central nervous system before formation of the blood-brain barrier. During development, proliferation of microglia in the brain requires the receptor tyrosine kinase colony-stimulating factor receptor 1 (CSFR1) (see Hughes and Bergles). Elmore et al. found that CSFR1 activity was also required for the survival of microglia in adult mice and uncovered a latent population of microglial progenitors that may contribute to immune homeostasis in the brain. Compared to mice fed with a normal diet and exposed to lipopolysaccharide (LPS) to induce neural inflammation, mice fed chow mixed with the CSFR1 inhibitor PLX3397 and exposed to LPS had decreased abundance of microglial markers, fewer microglia, and reduced expression of multiple genes encoding pro-inflammatory cytokines. Microglia in mice fed PLX3397 had a phagocytic-like morphology, were positive for cleaved-caspase 3, and stained with the cell-impermeable DNA dye propidium iodide, suggesting that they were undergoing apoptotic cell death. Depletion of microglia with PLX3397 did not affect the overall brain volume, performance on several behavioral tasks, the integrity of the blood-brain barrier, or the abundance of neuronal and oligodendrocytic markers, and increased the abundance of markers of astrogliosis, a process associated with neuroinflammation, without increasing the number of astrocytes. Mice fed PLX3397 for 7 days showed partial repopulation of microglia within 3 days after being switched back to a normal diet. Fate-mapping studies and comparative gene expression analysis of microglia-depleted and microglia-repopulated brains suggested that new microglia arose from proliferation of a brain-resident progenitor and not infiltration by peripheral macrophages. Thus, CSFR1 is required for microglial survival and homeostasis in the adult brain.

M. R. P. Elmore, A. R. Najafi, M. A. Koike, N. N. Dagher, E. E. Spangenberg, R. A. Rice, M. Kitazawa, B. Matusow, H. Nguyen, B. L. West, K. N. Green, Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron 82, 380–397 (2014). [Abstract]

E. G. Hughes, D. E. Bergles, Hidden progenitors replace microglia in the adult brain. Neuron 82, 253–255 (2014). [Abstract]