Overexpression of macrophage colony-stimulating factor receptor on microglial cells induces an inflammatory response

Microglia are important in the inflammatory response in Alzheimer's disease (AD). We showed previously that macrophage colony-stimulating factor recep tor (M-CSFR), encoded by the c-fins protooncogene, is overexpressed on micr oglia surrounding amyloid beta (A beta) deposits in the APP(V717F) mouse mo del for AD. The M-CSFR is also increased on microglia after experimental br ain injury and in AD. To determine the relevance of these findings, we tran siently expressed M-CSFR on murine BV-2 and human SV-A3 microglial cell lin es using an SV40-promoted c-fms construct. M-CSFR overexpression resulted i n microglial proliferation and increased expression of inducible nitric-oxi de synthase, the proinflammatory cytokines interleukin-1 alpha, macrophage inflammatory protein 1-alpha, and interleukin-6 and of macrophage colony-st imulating factor (M-CSF) itself. Antibody neutralization of M-CSF showed th at the M-CSFR-induced proinflammatory response was dependent on M-CSF in th e culture media. By using a co-culture of c-fins-transfected murine microgl ia and rat organotypic hippocampal slices and. a species-specific real time reverse transcriptase-polymerase chain reaction assay and enzyme-linked im munosorbent assay, we showed that M-CSFR overexpression on exogenous microg lia induced expression of interleukin-1 alpha by the organotypic culture. T hese results show that increased M-CSFR expression induces microglial proli feration, cytokine expression, and a paracrine inflammatory response, sugge sting that in APP(V717F) mice increased M-CSFR on microglia could be an imp ortant factor in Ap-induced inflammatory response.