CONICET | Buscador de Institutos y Recursos Humanos

Background: Ketamine, a NMDA antagonist, is still used as an anesthetic but recently is emerging as a fast and potent antidepressive drug. The biology of this effect is poorly understood but new research implicates that one of the main target of its action is the immune response. This associates with the concept that inflammationcontributesto the physiopathology of depression. Macrophages are key players in the balance of pro and antiinflammatory response; therefore, the aim of this study was to elucidate the effect of ketamine, type of receptor involved and gene program elicited on humanmacrophages during differentiation and polarization. Methods: Blood samples were drawn from healthy volunteers and mononuclear cells were isolated from the cellularfraction by Ficoll gradient. After CD14 positive selection, monocytes were cultured for 7 days and treated with ketamine at different time points (day 1 or 5). LPS+INFγ, IL-4 or dexamethasone were used as positive controls of macrophage polarization. To measure the inflammatory response, LPS was added ON in some experiments at day 6. Phenotype characterization was performed by FACS analysis and gene expression by qPCR. Results:We found that ketamine (0.1, 1 and 10 μM) induced an antiinflammatory profile on macrophages with high expression of CD163 and MERTK, intermediate levels of CD64 and no expression of CD206, compatible with a regulatory M2c-like phenotype. mRNA levels of TGM2 and CCL22 genes, related to a M2 profile, were also up-regulated in ketamine treated macrophages. Moreover, ketamine dampens macrophage activation, with lower expression of CD80 and HLADR and diminishes TNF-α production induced by LPS. Addition of MK801, a glutamate receptor antagonist, showed that the effect ismediated by NMDA receptors. Conclusions: These results show that ketamine not only dampens acute inflammation but also induces an antiinflammatory program on human monocytes skewing macrophages to a regulatory M2c-like profile.