A prophylactic effect of macrophage-colony stimulating factor on chronic stress-induced depression-like behaviors in mice

Innate immune activation has been shown to reduce the severity of nervous system disorders such as brain ischemia and traumatic brain damage. Macrophage-colony stimulating factor (M-CSF), a drug that is used to treat hematological system disease, is an enhancer of the innate immune response. In the present study, we evaluated the effect of M-CSF preconditioning on chronic social defeat stress (CSDS)-induced depression-like behaviors in mice. Results showed that a single M-CSF injection 1 day before stress exposure at the dose of 100 and 500 μg/kg, or a single M-CSF injection (100 μg/kg) 1 or 5 days but not 10 days before stress exposure prevented CSDS-induced depression-like behaviors in mice. Further analysis showed that a second M-CSF injection 10 days after the first M-CSF injection and a 2 × or 4 × M-CSF injections 10 days before stress exposure also prevented CSDS-induced depression-like behaviors. Molecular studies revealed that a single M-CSF injection prior to stress exposure skewed the neuroinflammatory responses in the brain in CSDS-exposed mice towards an anti-inflammatory phenotype. These behavioral and molecular actions of M-CSF were correlated with innate immune stimulation, as pre-inhibiting the innate immune activation by minocycline pretreatment (40 mg/kg) abrogated the preventive effect of M-CSF on CSDS-induced depression-like behaviors and neuroinflammatory responses. These results provide evidence to show that innate immune activation by M-CSF pretreatment may prevent chronic stress-induced depression-like behaviors via preventing the development of neuroinflammatory response in the brain, which may help to develop novel strategies for the prevention of depression.