MSC Modulate Peripheral Stress-Induced Innate Immune Activation Indirectly Limiting the Emergence of Neuroinflammation and Depressive / Anxiety-like Behaviors

Abstract Background Hyperactivation of innate immunity has been implicated in the etiology of mood disorders, including major depressive disorder (MDD). Mesenchymal Stromal Cells (MSC) have demonstrated potent immunomodulatory capabilities in the context of chronic inflammatory disease and injury but have yet to be evaluated in stress-based preclinical models of MDD. We sought to test the ability of intravenous MSC to modulate innate immune activation and behavioral patterns associated with repeated social defeat (RSD). Methods Murine RSD-induced innate immune activation as well as depressive and anxiety-like behaviors were assessed in unstressed, RSD and RSD + human MSC groups. Biodistribution and fate studies were performed to inform potential mechanisms of action. Results MSC reduced stress-induced circulating pro-inflammatory cytokines, monocytes, neuroinflammation and depressive / anxiety-like behaviors. Biodistribution analyses indicated that infused MSC distributed within peripheral organs without homing to the brain. Murine neutrophils targeted MSC in the lungs within hours of administration. MSC and recipient neutrophils were cleared by recipient macrophages promoting a switch towards a regulatory phenotype and systemic resolution of inflammation. Conclusions Peripheral delivery of MSC modulates CNS inflammatory processes and aberrant behavioral patterns in a stress-based rodent model of MDD and anxiety. Recent studies suggest that host immune cell-mediated phagocytosis of MSC in vivo can trigger an immunomodulatory cascade, resulting in resolution of inflammation. Our data suggest that similar mechanisms may protect distal organs, including the brain, from systemic, stress-induced pro-inflammatory spikes and may uncover unexpected targets in the periphery for novel or adjunct treatment for a subset of MDD patients.