Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China; Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 200032 Shanghai, People's Republic of China.
Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China.
Int Immunopharmacol. 2021 Jul;96:107744. doi: 10.1016/j.intimp.2021.107744. Epub 2021 May 13.
A wealth of evidence indicate that the peripheral immune activation alters brain development. However, it is still largely unclear whether and how peripheral immunosuppression affects neurodevelopment. Here, we found that the immunosuppressant cyclosporin A (CsA) decreased the number of BrdU+, BrdU+/DCX+, BrdU+/NeuN + cells in the hippocampus, impaired learning and memory and inhibited protein levels of the shh signaling pathway, including Shh, Smo and Gli1. However, the shh pathway receptor agonist SAG could block the impairment of cognitive ability and the decrease of hippocampal neurogenesis and brain-derived neurotrophic factor (BDNF) level induced by CsA. We also found that CsA decreased the level of interferon-gamma (IFN-γ), while up-regulation of IFN-γ altered the inhibitory effect of the shh signaling pathway and the decrease of BDNF induced by CsA. Collectively, these data indicate that peripheral CsA impairs neurogenesis and cognition in brain development through downregulating the IFN-γ-Shh-BDNF pathway. The present study guides us to correctly apply immunomodulatory drugs in early life and suggests that the IFN-γ-Shh-BDNF pathway may represent a novel protective target for neurodevelopment under the condition of immunosuppression.
大量证据表明，外周免疫激活会改变大脑发育。然而，外周免疫抑制是否以及如何影响神经发育仍在很大程度上不清楚。在这里，我们发现免疫抑制剂环孢素 A (CsA) 减少了海马体中 BrdU+、BrdU+/DCX+、BrdU+/NeuN+细胞的数量，损害了学习和记忆能力，并抑制了 shh 信号通路的蛋白水平，包括 Shh、Smo 和 Gli1。然而，shh 通路受体激动剂 SAG 可以阻断 CsA 引起的认知能力障碍、海马神经发生减少和脑源性神经营养因子 (BDNF) 水平降低。我们还发现 CsA 降低了干扰素-γ (IFN-γ) 的水平，而 IFN-γ 的上调改变了 shh 信号通路的抑制作用以及 CsA 引起的 BDNF 减少。总的来说，这些数据表明，外周 CsA 通过下调 IFN-γ-Shh-BDNF 通路损害大脑发育中的神经发生和认知。本研究指导我们正确地在生命早期应用免疫调节药物，并表明 IFN-γ-Shh-BDNF 通路可能代表免疫抑制下神经发育的一个新的保护靶点。
