title: CSF1 overexpression has pleiotropic effects on microglia in vivo.
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.
authors.affiliation: Pharmaceutical 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.
authors.forename: Ishani
authors.initials: I
authors.lastname: De
authors.forename: Maria
authors.initials: M
authors.lastname: Nikodemova
authors.forename: Megan D
authors.initials: MD
authors.lastname: Steffen
authors.forename: Emily
authors.initials: E
authors.lastname: Sokn
authors.forename: Vilena I
authors.initials: VI
authors.lastname: Maklakova
authors.forename: Jyoti J
authors.initials: JJ
authors.lastname: Watters
authors.forename: Lara S
authors.initials: LS
authors.lastname: Collier
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001933:Brain Stem / Q000166:cytology; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002531:Cerebellum / Q000166:cytology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D058685:Genetic Pleiotropy / Q000187:drug effects / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D007211:Indoles / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: C491049:Aif1 protein, mouse; D039481:CD11b Antigen; D002135:Calcium-Binding Proteins; D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D007211:Indoles; D008070:Lipopolysaccharides; D008840:Microfilament Proteins; C528407:PLX 4720; D012333:RNA, Messenger; D013449:Sulfonamides; D049452:Green Fluorescent Proteins; D016173:Macrophage Colony-Stimulating Factor
keywords: Csf1 (Mcsf); M1 M2 polarization; PLX3397; microglia