Zhang Aomei, Zhang Xinxin, Tang Xiaohan, Liu Ming, Xie Jialing, Li Suyun, Cao Wenyu, Zhou Huamao, Xu Yang
Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
Hengyang Medical School, The Affiliated NanHua Hospital, University of South China, Hengyang, 421000, Hunan, China.
Mol Neurobiol. 2025 Jul 11. doi: 10.1007/s12035-025-05187-8.
The comorbidity of anxiety and depression frequently occurs in patients with inflammatory pain, which requires further investigation. Previous evidence supports a close link between Complement Component 3 (C3) and affective disorders; however, whether C3 is involved in inflammatory pain-induced anxiodepression remains unclear. Using a mouse inflammatory pain model with Complete Freund's Adjuvant (CFA), we observed that the animals exhibited significant anxiodepression-like behaviors and that the expression of hippocampal C3 was obviously increased three weeks after CFA injection. Microinjection of the AAV vector that downregulates C3 into the hippocampus alleviated anxiodepression-like behaviors. Moreover, we noted that knocking down hippocampal C3 partially alleviated pain behavior in CFA-treated mice. Mechanistically, we found that the benefit of knocking down the hippocampal C3 may be due to inhibition of its downstream C3aR-GSK3β signaling pathway and restoration of glia activation and inflammatory response to levels similar to those found under non-inflammatory conditions. Consequently, our work reveals the critical role of the hippocampal C3/C3aR-GSK3β signaling pathway in inflammatory pain-induced anxiodepression-like behaviors, suggesting that C3/C3aR-GSK3β signaling is a potential therapeutic target for inflammatory pain-induced mental health conditions.
焦虑和抑郁的共病现象在炎性疼痛患者中经常出现，这需要进一步研究。先前的证据支持补体成分3（C3）与情感障碍之间存在密切联系；然而，C3是否参与炎性疼痛诱导的焦虑抑郁尚不清楚。使用完全弗氏佐剂（CFA）建立小鼠炎性疼痛模型，我们观察到动物表现出明显的焦虑抑郁样行为，并且在CFA注射三周后海马C3的表达明显增加。向海马内微量注射下调C3的腺相关病毒载体可减轻焦虑抑郁样行为。此外，我们注意到敲低海马C3可部分减轻CFA处理小鼠的疼痛行为。从机制上讲，我们发现敲低海马C3的益处可能是由于抑制其下游的C3aR-GSK3β信号通路，并使神经胶质细胞激活和炎症反应恢复到与非炎症条件下相似的水平。因此，我们的研究揭示了海马C3/C3aR-GSK3β信号通路在炎性疼痛诱导的焦虑抑郁样行为中的关键作用，表明C3/C3aR-GSK3β信号通路是炎性疼痛诱导的心理健康状况的潜在治疗靶点。
