CSF1 overexpression 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 overexpression on microglia, transgenic mice that overexpress CSF1 in the glial fibrillary acidic protein (GFAP) compartment were generated. CSF1 overexpressing mice have increased microglial proliferation and increased microglial numbers compared with 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 overexpressing and control mice. Microglia in CSF1 overexpressing 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. These results indicate that the CSF1 overexpression 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. GLIA 2014;62:1955–1967 Main Points CSF1 over‐expression in the GFAP compartment was found to modulate microglial proliferation and response to LPS. An inhibitor of CSF1R promoted microglial apoptosis, indicating that signaling through CSF1R is required for adult microglial survival.