Macrophage-colony stimulating factor as an inducer of microglial proliferation in axotomized rat facial nucleus

P>We analyzed the mechanism of microglial proliferation in rat axotomized facial nucleus (axotFN). In immunoblotting analysis for possible mitogens, we noticed that the amounts of macrophage-colony stimulating factor (M-CSF) increased in the axotFN for 3-7 days after transection. In contrast, the amounts of granulocyte macrophage-CSF and interleukin-3 did not significantly increase. A potential source for M-CSF was immunohistochemically verified to be microglia. Immunoblotting showed that the amounts of receptor for M-CSF (cFms) increased in the axotFN for 3-14 days after injury, and immunohistochemical staining showed that cFms is expressed in microglia. Proliferating cell nuclear antigen as a marker of proliferation was immunohistochemically identified in microglia in axotFN, and the level was found to peak 3 days after transection in immunoblotting. Hypothesizing that up-regulated M-CSF triggers the above phenomena, we investigated the effects of M-CSF on cFms and proliferating cell nuclear antigen levels in primary microglia. The biochemical experiments revealed that M-CSF induces cFms and drives the cell cycle in microglia. The neutralization of M-CSF in microglia derived from axotFN significantly reduced the proliferation. These results demonstrate that up-regulated M-CSF triggers the induction of cFms in microglia and causes the microglia to proliferate in the axotFN.