Adipose-derived mesenchymal stem cells protect against CMS-induced depression-like behaviors in mice via regulating the Nrf2/HO-1 and TLR4/NF-κB signaling pathways

• Published in: Acta pharmacologica Sinica 2020-05, Vol.41 (5), p.612-619
• Main Authors: Huang, Xiao, Fei, Guo-qiang, Liu, Wen-juan, Ding, Jing, Wang, Yuan, Wang, Hao, Ji, Jian-lin, Wang, Xin
• Format: Article
• Language: English
• Subjects: Animals; Anti-inflammatory agents; Anti-Inflammatory Agents, Non-Steroidal - metabolism; Antidepressants; Biomedical and Life Sciences; Biomedicine; Brain-derived neurotrophic factor; Cells, Cultured; Depression - metabolism; Disease Models, Animal; Heme Oxygenase-1 - metabolism; IL-1β; Immunology; Inflammatory diseases; Interleukin 6; Internal Medicine; Lipopolysaccharides; Male; Medical Microbiology; Membrane Proteins - metabolism; Mental depression; Mental disorders; Mesenchymal stem cells; Mesenchymal Stem Cells - metabolism; Mice; Mice, Inbred C57BL; Microglia; Microglial cells; Monocyte chemoattractant protein 1; Neuroprotection; NF-E2-Related Factor 2 - metabolism; NF-kappa B - metabolism; NF-κB protein; Pharmacology/Toxicology; Phenotypes; Polarization; Signal Transduction; Stem cell transplantation; Stem cells; Stress, Psychological - metabolism; Sucrose; TLR4 protein; Toll-Like Receptor 4 - metabolism; Toll-like receptors; TrkB receptors; Tumor necrosis factor-α; Vaccine
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/s41401-019-0317-6

Increasing studies show that inflammatory processes may be involved in depressive disorders. Nuclear factor erythroid-2 related factor 2 (Nrf2) modulates tissue microglial M1 phenotypic changes to the M2 phenotype, which is implicated in protection against inflammatory diseases. We have reported that the adipose-derived mesenchymal stem cells (ADSCs) display anti-inflammatory activity. In this study we explored whether the mechanism of anti-inflammatory activity of ADSCs was related to Nrf2. ADSCs were isolated from mouse fat pads and intravenously administered to chronic mild stress (CMS)-exposed C57BL/6 mice at the dose of 1 × 10 6 once a week for 3 weeks. We showed that ADSC administration significantly remedied CMS-induced depressive-like behaviors in sucrose preference test, tail suspension test, and forced swim test accompanied by suppressing microglial activation and the expression of inflammatory factors including MCP-1, TNF-α, IL-1β, and IL-6. Furthermore, ADSC administration promoted both the expression of BDNF and TrkB, and promoted Nrf2/HO-1 signaling but suppressed TLR4/NF-κB signaling in brain tissue. In order to elucidate the role of Nrf2/HO-1 signaling in ADSC-caused neuroprotection, Nrf2-modified ADSCs were cocultured with BV2 microglial cells, then exposed to lipopolysaccharide (LPS). Downregulation of Nrf2 in ADSCs decreased the protective effects of ADSCs against LPS-induced microglial activation and M1 polarization. Nrf2 overexpression in ADSCs markedly suppressed LPS-induced TLR4 and NF-κB expression in microglial cells. These results suggest a possible antidepressive mechanism correlated with microglial polarization for anti-inflammatory agents, which may provide a new microglia-targeted strategy for depression therapy.