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Expression of macrophage colony-stimulating factor and its receptor in microglia activation is linked to
1Molecular Neurobiology Laboratory, Department of Anatomy, Faculty of Medicine, National University of Singapore, Singapore.
Abstract:
Prenatal exposure to teratogen agents is linked to the pathogenesis of neurodevelopment disorders, but the mechanisms leading to the neurodevelopmental disturbance are poorly understood. To elucidate this, an in vitro model of microglial activation induced by neuronal injury has been characterized. In this connection, exposure of primary microglial cells to the conditioned medium from the neuronal damage induced by teratogen, cyclophosphamide, is accompanied by a reactive microgliosis as assessed by reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, lectin histochemistry, double labeling immunohistochemistry and in situ hybridization. Our results showed that reactive microglia were capable of releasing various cytokines such as tumor necrosis factor-alpha, interleukin-1, interleukin-6, transforming growth factor-beta and nitric oxide. Also, we have shown that macrophage colony-stimulating factor (M-CSF) was in fact produced by the reactive microglia. Concomitant to this was the increased expression of M-CSF receptor in these cells following the teratogen-induced neuronal injury. The up-regulation of M-CSF receptor suggests that the cells are capable of responding to self-derived M-CSF in an autocrine fashion. Results with antibody neutralization further suggest that microglial proinflammatory response, as manifested by cytokine expression in culture, is mediated by M-CSF, which acts as a molecular signal that initiates a microglial reaction. We therefore suggest that microglial activation following cyclophosphamide treatment is not only a response to the neuronal damage, but is also a cause of the damage during pathogenesis of neurodevelopment disorders. To this end, the increased expression of M-CSF and its receptor on microglia would be directly linked to the active cell proliferation and proinflammatory response in the teratogen-induced injury.
Insights
Teratogen exposure during pregnancy can harm fetal brain development. This study reveals that activated microglia, triggered by neuronal damage, contribute to this harm, potentially causing neurodevelopmental disorders.
Area of Science:
- Neuroscience
- Developmental Biology
- Immunology
Background:
- Prenatal exposure to teratogens is linked to neurodevelopmental disorders.
- The precise mechanisms underlying teratogen-induced neurodevelopmental disturbances remain unclear.
Purpose of the Study:
- To investigate the role of microglial activation in response to teratogen-induced neuronal injury.
- To elucidate the molecular mechanisms by which microglia contribute to neurodevelopmental pathogenesis.
Main Methods:
- Utilized an in vitro model of microglial activation induced by neuronal damage from cyclophosphamide exposure.
- Employed techniques including RT-PCR, ELISA, lectin histochemistry, immunohistochemistry, and in situ hybridization.
- Investigated cytokine release and macrophage colony-stimulating factor (M-CSF) signaling pathways.
Main Results:
- Teratogen-induced neuronal injury activated primary microglial cells, leading to reactive microgliosis.
- Reactive microglia released pro-inflammatory cytokines (TNF-α, IL-1, IL-6, TGF-β) and nitric oxide.
- Macrophage colony-stimulating factor (M-CSF) was produced by reactive microglia, with increased M-CSF receptor expression suggesting autocrine signaling.
Conclusions:
- Microglial activation, mediated by M-CSF, plays a dual role: responding to neuronal damage and actively contributing to its pathogenesis.
- This microglial response, characterized by cytokine release and M-CSF signaling, is implicated in the development of neurodevelopmental disorders following teratogen exposure.