Granulocyte-macrophage colony-stimulating factor-triggered innate immune tolerance against chronic stress-induced behavioral abnormalities in mice

•GM-CSF preconditioning prevents CSDS-induced depression-like behaviors.•GM-CSF preconditioning prevents CSDS-induced anxiety-like behaviors.•GM-CSF preconditioning prevents the neuroinflammatory responses in CSDS mice.•Minocycline abrogates the effect of GM-CSF on CSDS-induced abnormal behaviors.•Minocycline abrogates the effect of GM-CSF on neuroinflammation in CSDS mice. Pre-stimulation of the innate immune is considered a potential strategy to prevent chronic stress-induced behavioral abnormalities in animals. In this study, we investigated whether granulocyte–macrophage colony-stimulating factor (GM-CSF), an immunostimulant used in the clinic to treat diseases of the hematopoietic system, can prevent chronic stress-induced behavioral abnormalities in mice. Our results showed that a single intraperitoneal injection of GM-CSF (100 μg/kg) one day before stress exposure prevented the depression- and anxiety-like behaviors induced by chronic social defeat stress (CSDS) in mice, including preventing the CSDS-induced increase in the immobility time in the tail suspension test and forced swimming test and decrease in the time spent in the interaction zone in the social interaction test, as well as preventing the CSDS-induced decrease in the time spent (i) in open arms in the elevated plus maze test, (ii) on the illuminated side in the light–dark test, and (iii) in the central region of the open field test. The single GM-CSF preinjection (100 μg/kg) also prevented the CSDS-induced increase in the expression levels of interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α) mRNA in the hippocampus and medial prefrontal cortex of the mice. Further analysis showed that the preventive effect of GM-CSF on CSDS-induced depression- and anxiety-like behaviors and neuroinflammatory responses was abolished by pretreatment with minocycline (an innate immune inhibitor). These results indicate that a single low dose of GM-CSF before injection could be a potential way to prevent behavioral abnormalities induced by chronic stress in mice.