CSF1 over-expression has pleiotropic effects on microglia in vivo

Macrophage colony stimulating factor (CSF1) is a cytokine that is upregulated in several diseases of the central nervous system (CNS). To examine the effects of CSF1 over-expression on microglia, transgenic mice that over-express CSF1 in the glial fibrillary acidic protein (GFAP) compartment were generated. CSF1 over-expressing mice have increased microglial proliferation and increased microglial numbers compared to controls. Treatment with PLX3397, a small molecule inhibitor of the CSF1 receptor CSF1R and related kinases, decreases microglial numbers by promoting microglial apoptosis in both CSF1 over-expressing and control mice. Microglia in CSF1 over-expressing mice exhibit gene expression profiles indicating that they are not basally M1 or M2 polarized, but they do have defects in inducing expression of certain genes in response to the inflammatory stimulus lipopolysaccharide (LPS). These results indicate that the CSF1 over-expression observed in CNS pathologies likely has pleiotropic influences on microglia. Furthermore, small molecule inhibition of CSF1R has the potential to reverse CSF1-driven microglial accumulation that is frequently observed in CNS pathologies, but can also promote apoptosis of normal microglia.