Department of Anesthesiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China.
Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Int Immunopharmacol. 2020 Oct;87:106814. doi: 10.1016/j.intimp.2020.106814. Epub 2020 Jul 21.
Systemic inflammation induces cognitive impairments via unclear mechanisms. Increasing evidence has suggested complement C3/C3a receptor signaling, a key component of innate immune pathogen defense, plays an important role in cognition and neurodegeneration, whereas its dysfunction is implicated in many neurological disorders. However, it remains unclear whether complement C3/C3a receptor signaling was involved in systemic inflammation-induced cognitive impairments. In the present study, we showed that hippocampal complement C3 levels in astrocytes and C3a receptor expressions in microglia were specifically up-regulated after lipopolysaccharide (LPS) injection. Interestingly, LPS selectively induced inhibitory but not excitatory synapse related protein loss. Notably, C3a receptor antagonist SB290157 trifluoroacetate attenuated LPS-induced hippocampal neuroinflammation and inhibitory synapse related protein loss, contributing to improved cognitive function. In conclusion, our study suggests that complement C3/C3a receptor signaling plays a key role in LPS-induced cognitive impairments, which may serve a therapeutic target for systemic inflammation related cognitive disorders.
系统性炎症通过不明机制引起认知障碍。越来越多的证据表明，补体 C3/C3a 受体信号转导，先天免疫病原体防御的关键组成部分，在认知和神经退行性变中发挥重要作用，而其功能障碍与许多神经紊乱有关。然而，补体 C3/C3a 受体信号转导是否参与系统性炎症引起的认知障碍仍不清楚。在本研究中，我们发现脂多糖（LPS）注射后星形胶质细胞中的海马补体 C3 水平和小胶质细胞中的 C3a 受体表达特异性上调。有趣的是，LPS 选择性诱导抑制但不诱导兴奋性突触相关蛋白丢失。值得注意的是，补体 C3a 受体拮抗剂 SB290157 三氟乙酸减弱 LPS 诱导的海马神经炎症和抑制性突触相关蛋白丢失，有助于改善认知功能。总之，我们的研究表明，补体 C3/C3a 受体信号在 LPS 诱导的认知障碍中起关键作用，可能成为与系统性炎症相关的认知障碍的治疗靶点。
