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Background: Some types of cell-based therapies may reduce secondary brain injury after stroke by modulating immune responses from the spleen. Here, we hypothesized that fractalkine (FKN; CX3CL1) derived from the spleen mediates cross-talk between the spleen and brain, and that upregulation of FKN in the spleen by bone marrow mononuclear cells (MNCs) is an important mechanism underlying how MNCs enhance recovery after stroke.Methods: To model ischemic stroke, we employed rat and mouse middle cerebral artery occlusion (MCAo) models. 24 hours after MCAo, animals received autologous MNCs IV or saline as vehicle controls. Brains and spleens were harvested and serum was collected at various time points after MCAo. FKN gene expression and protein levels were measured. Functional testing was evaluated for up to 28d after MCAo. In parallel experiments, mice were subjected to splenectomy two weeks prior to MCAo and the same experiments were repeated in animals without a spleen. In another experiment, antibody neutralizing FKN receptor (anti-CX3CR1) was injected ICV at 1 hour after MNC to evaluate the impact of blocking the FKN receptor in the brain.Results: MNC treatment significantly increased FKN levels in the spleen, serum and brain starting 1 day after MNC treatment, as compared to the vehicle-treated group. Splenectomy significantly attenuated FKN upregulation in response to MNC administration, and also attenuated the treatment-mediated effects on functional recovery. ICV injection of anti-CX3CR1 also abolished the MNCs-mediated beneficial effect on stroke recovery. In cell culture experiment, MNCs increased soluble FKN release by spenocytes and this process required physical MNC-splenocyte interaction and was dependent on the presence of IFN-γ.Conclusion: MNCs enhance stroke recovery through mechanisms involving the spleen; FKN may be one of the important signals mediating the cross-talk between the spleen and the brain.