Overexpression of Macrophage Colony-stimulating Factor Receptor on Microglial Cells Induces an Inflammatory Response

• Published in: The Journal of biological chemistry 2001-08, Vol.276 (32), p.30142-30149
• Main Authors: Mitrasinovic, O M, Perez, G V, Zhao, F, Lee, Y L, Poon, C, Murphy, Jr, G M
• Format: Article
• Language: English
• Subjects: Amidohydrolases; Aminopeptidases - metabolism; Animals; Blotting, Western; c-fms gene; Cell Division; Cell Line; Coculture Techniques; Enzyme-Linked Immunosorbent Assay; Hippocampus - metabolism; Humans; Immunohistochemistry; Inflammation; interleukin 1^b; Interleukin-1 - metabolism; Interleukin-6 - metabolism; Kinetics; L-Lactate Dehydrogenase - metabolism; Macrophage Colony-Stimulating Factor - metabolism; macrophage colony-stimulating factor receptors; macrophage inflammatory protein 1^a; Mice; Microglia - metabolism; Nitric Oxide Synthase - metabolism; Nitric Oxide Synthase Type II; Polymerase Chain Reaction; Protein Binding; Rats; Receptor, Macrophage Colony-Stimulating Factor - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; Time Factors; Transfection
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M104265200

Microglia are important in the inflammatory response in Alzheimer's disease (AD). We showed previously that macrophage colony-stimulating factor receptor (M-CSFR), encoded by the c- fms protooncogene, is overexpressed on microglia surrounding amyloid β (Aβ) deposits in the APP V717F mouse model for AD. The M-CSFR is also increased on microglia after experimental brain injury and in AD. To determine the relevance of these findings, we transiently expressed M-CSFR on murine BV-2 and human SV-A3 microglial cell lines using an SV40-promoted c- fms construct. M-CSFR overexpression resulted in microglial proliferation and increased expression of inducible nitric-oxide synthase, the proinflammatory cytokines interleukin-1α, macrophage inflammatory protein 1-α, and interleukin-6 and of macrophage colony-stimulating factor (M-CSF) itself. Antibody neutralization of M-CSF showed that the M-CSFR-induced proinflammatory response was dependent on M-CSF in the culture media. By using a co-culture of c- fms -transfected murine microglia and rat organotypic hippocampal slices and a species-specific real time reverse transcriptase-polymerase chain reaction assay and enzyme-linked immunosorbent assay, we showed that M-CSFR overexpression on exogenous microglia induced expression of interleukin-1α by the organotypic culture. These results show that increased M-CSFR expression induces microglial proliferation, cytokine expression, and a paracrine inflammatory response, suggesting that in APP V717F mice increased M-CSFR on microglia could be an important factor in Aβ-induced inflammatory response.