Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Jiangsu, China.
Department of Neurology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
Brain Behav Immun. 2021 May;94:225-234. doi: 10.1016/j.bbi.2021.02.004. Epub 2021 Feb 16.
A growing body of studies indicated that exosomes are one of vital players in pathological process of neuropsychiatric diseases, but their role in major depressive disorder (MDD) remains poorly understood. Here we purified plasma exosomes from depression including lipopolysaccharide (LPS)-challenged depression, chronic restraint stress (CRS)-induced depression, MDD subjects, and from control mice or volunteers. The therapeutic effect of these exogenous exosomes was assessed utilizing behavioral tests and biochemical approaches in the LPS-caused depression or microglial BV2 cells. The expression of exosomal sigma-1 receptor (Sig-1R) was evaluated by western blotting. The role of Sig-1R in the biological function of exosomes was determined using Sig-1R knockout mice and HEK 293 cells. Our results revealed that injection of exosomes from depression models or patients rather than normal controls significantly ameliorated depressive-like behaviors, deficiency of BDNF expression and neuro-inflammation in LPS-challenged mice. In addition, co-culture with exosomes from depression models or patients instead of from controls prevented LPS-induced inflammation responses in microglial BV2 cells. Moreover, Sig-1R was demonstrated for the first time to significantly be enriched in exosomes from depression models or patients compared with that from normal controls. However, Sig-1R null exosomes no longer emerged antidepressant-like action in LPS-challenged mice. Thus, we demonstrated that plasma exosomes from depression exerted antidepressant-like effects in a Sig-1R dependent manner in the LPS-induced depression. This work improves our understanding of the exosomes in depression, suggesting a novel exosomes-based approach for MDD treatment.
越来越多的研究表明，外泌体是神经精神疾病病理过程中的重要参与者之一，但它们在重度抑郁症（MDD）中的作用仍知之甚少。在这里，我们从包括脂多糖（LPS）诱导的抑郁症、慢性束缚应激（CRS）诱导的抑郁症、MDD 患者以及对照小鼠或志愿者中纯化了血浆外泌体。通过 LPS 诱导的抑郁症或小胶质细胞 BV2 细胞中的行为测试和生化方法评估了这些外源性外泌体的治疗效果。通过 Western blot 评估外泌体 sigma-1 受体（Sig-1R）的表达。使用 Sig-1R 敲除小鼠和 HEK 293 细胞确定 Sig-1R 在外泌体生物学功能中的作用。我们的结果表明，与正常对照相比，来自抑郁症模型或患者的外泌体注射而非正常对照显著改善了 LPS 诱导的抑郁样行为、BDNF 表达缺陷和神经炎症。此外，与对照共培养而不是来自对照的外泌体可以防止 LPS 诱导的小胶质细胞 BV2 细胞炎症反应。此外，首次证明 Sig-1R 明显富集于与正常对照相比来自抑郁症模型或患者的外泌体中。然而，Sig-1R 缺失的外泌体不再在 LPS 诱导的抑郁小鼠中产生抗抑郁样作用。因此，我们证明了来自抑郁症的血浆外泌体以 Sig-1R 依赖的方式在 LPS 诱导的抑郁症中发挥抗抑郁样作用。这项工作提高了我们对抑郁症中外泌体的认识，为 MDD 的治疗提供了一种新的基于外泌体的方法。
