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 × 106 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.

中文翻译：

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脂肪来源的间充质干细胞可通过调节Nrf2 / HO-1和TLR4 /NF-κB信号通路来预防CMS诱导的小鼠抑郁样行为。

越来越多的研究表明，炎症过程可能与抑郁症有关。核因子erythroid-2相关因子2（Nrf2）将组织小胶质细胞M1表型改变为M2表型，这与预防炎症性疾病有关。我们已经报道了脂肪来源的间充质干细胞（ADSCs）显示出抗炎活性。在这项研究中，我们探讨了ADSCs抗炎活性的机制是否与Nrf2有关。从小鼠脂肪垫中分离出ADSC，并每周一次以1×106的剂量静脉内对暴露于慢性轻度应激（CMS）的C57BL / 6小鼠进行静脉给药，持续3周。我们发现，在蔗糖偏好测试，尾部悬浮测试，强迫游泳试验并伴有抑制小胶质细胞活化和MCP-1，TNF-α，IL-1β和IL-6等炎症因子的表达。此外，ADSC施用促进了脑组织中BDNF和TrkB的表达，并促进了Nrf2 / HO-1信号传导，但抑制了TLR4 /NF-κB信号传导。为了阐明Nrf2 / HO-1信号在ADSC引起的神经保护中的作用，将Nrf2修饰的ADSC与BV2小胶质细胞共培养，然后暴露于脂多糖（LPS）。ADSC中Nrf2的下调降低了ADSC对LPS诱导的小胶质细胞激活和M1极化的保护作用。NSC中的Nrf2过表达显着抑制了LPS诱导的小胶质细胞中TLR4和NF-κB的表达。