CSF1 overexpression has pleiotropic effects on microglia in vivo
Ishani De1, Maria Nikodemova, Megan D Steffen
1Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin Carbone Comprehensive Cancer Center and the Molecular and Cellular Pharmacology Graduate Program, University of Wisconsin-Madison, Madison, Wisconsin, 53705.
Abstract:
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.
Insights
Macrophage colony stimulating factor (CSF1) overexpression in the central nervous system (CNS) increases microglia. Inhibiting the CSF1 receptor (CSF1R) reduces microglia numbers but can also cause apoptosis.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Macrophage colony stimulating factor (CSF1) is a cytokine implicated in central nervous system (CNS) diseases.
- Microglia, the resident immune cells of the CNS, are affected by CSF1 levels.
Purpose of the Study:
- To investigate the impact of CSF1 overexpression on microglia in the CNS.
- To evaluate the efficacy of CSF1 receptor (CSF1R) inhibition on CSF1-driven microglial changes.
Main Methods:
- Generation of transgenic mice overexpressing CSF1 in the glial fibrillary acidic protein (GFAP) compartment.
- Treatment of mice with PLX3397, a CSF1R inhibitor.
- Analysis of microglial proliferation, apoptosis, and gene expression profiles.
Main Results:
- CSF1 overexpression led to increased microglial proliferation and numbers.
- PLX3397 treatment reduced microglial numbers in both CSF1-overexpressing and control mice by inducing apoptosis.
- Microglia in CSF1-overexpressing mice showed altered gene expression, lacking M1/M2 polarization and exhibiting defects in response to lipopolysaccharide.
Conclusions:
- CSF1 overexpression has diverse effects on microglia in the CNS.
- CSF1R inhibition can mitigate CSF1-induced microglial accumulation but also affects normal microglia populations through apoptosis.
