Mesenchymal Stromal Cells Modulate Peripheral Stress-Induced Innate Immune Activation Indirectly Limiting the Emergence of Neuroinflammation-Driven Depressive and Anxiety-like Behaviors
Autor: | Maxwell Charlat, Andrée Gauthier-Fisher, Fyyaz Siddiqui, Joseph Fish, Clifford Librach, Siddiq Moolla, Emaan Chaudry, Denis Gallagher |
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Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Inflammation Anxiety Monocytes Proinflammatory cytokine Cell therapy Social defeat Mice 03 medical and health sciences 0302 clinical medicine Immune system medicine Animals Humans Tissue Distribution Cells Cultured Biological Psychiatry Neuroinflammation Cell Proliferation Behavior Innate immune system Depression business.industry Macrophages Mesenchymal stem cell Mesenchymal Stem Cells Immunity Innate Disease Models Animal 030104 developmental biology Immunology Cytokines medicine.symptom business Biomarkers 030217 neurology & neurosurgery |
Zdroj: | Biological Psychiatry. 86:712-724 |
ISSN: | 0006-3223 |
Popis: | Background Hyperactivation of innate immunity has been implicated in the etiology of mood disorders, including major depressive disorder (MDD). Mesenchymal stromal cells (MSCs) 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 MSCs 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 MSCs reduced stress-induced circulating proinflammatory cytokines, monocytes, neuroinflammation, and depressive and anxiety-like behaviors. Biodistribution analyses indicated that infused MSCs distributed within peripheral organs without homing to the brain. Murine neutrophils targeted MSCs in the lungs within hours of administration. MSCs and recipient neutrophils were cleared by recipient macrophages promoting a switch toward a regulatory phenotype and systemic resolution of inflammation. Conclusions Peripheral delivery of MSCs modulates central nervous system 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 MSCs 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 proinflammatory spikes and may uncover unexpected targets in the periphery for novel or adjunct treatment for a subset of patients with MDD. |
Databáze: | OpenAIRE |
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