Meng Qian, Guo Meng-Hui, Zhang Rui, Wei Jing, Chen Qian, Zhao Xue-Chun, Xu Cai-Qi, Wu Yao-Yao, Kuai Jia-Jie, Zhao Jie-Min, Wu Yu-Jing, Ye Chong-Huan, Wei Hong-Rui, Zhu Xia, Jin Yan, Zhang Zhi, Wei Wei
Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Anhui Medical University, Key laboratory of Anti-Inflammatory and Immune Medicine (Anhui Medical University), Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, 230032, China.
CAS Key Laboratory of Brain Function and Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China.
Acta Pharmacol Sin. 2025 Jul 21. doi: 10.1038/s41401-025-01621-8.
Rheumatoid arthritis with depressive symptoms is frequently encountered in clinic. In this study, we investigated the molecular mechanisms responsible for comorbid depression with rheumatoid arthritis in collagen-induced arthritis (CIA) model mice. We showed that depression-like behaviors were developed at 5 weeks after establishing CIA model. Furthermore, we found that in the hippocampus of CIA mice, G-protein coupled receptor kinase 2 (GRK2) was significantly upregulated, while the expression of its target, corticotropin releasing hormone receptor 1 (CRHR1) was notably decreased, as was the downstream cAMP/PKA/CREB/BDNF signaling. We demonstrated that GRK2 could directly interact with CRHR1, suppressing CRHR1-dependent signaling. Knockdown of hippocampal GRK2 or pharmacological inhibition with CP-25 (35 mg·kg·d, i.g. for 21 days) could alleviate the depression-like behaviors in CIA mice, whereas GRK2 overexpression induced depression-like behaviors in naive mice. Our study identifies hippocampal GRK2 as a regulator of depression-like behaviors associated with rheumatoid arthritis in CIA model mice, suggesting both a therapeutic target and potential treatment strategy.
类风湿关节炎伴抑郁症状在临床上屡见不鲜。在本研究中，我们在胶原诱导的关节炎（CIA）模型小鼠中探究了类风湿关节炎合并抑郁症的分子机制。我们发现，在建立CIA模型5周后出现了类似抑郁的行为。此外，我们发现，在CIA小鼠的海马体中，G蛋白偶联受体激酶2（GRK2）显著上调，而其靶点促肾上腺皮质激素释放激素受体1（CRHR1）的表达则明显下降，下游的cAMP/PKA/CREB/BDNF信号传导也出现下降。我们证明，GRK2可直接与CRHR1相互作用，抑制CRHR1依赖的信号传导。敲低海马体中的GRK2或用CP-25（35mg·kg·d，灌胃21天）进行药物抑制可减轻CIA小鼠的类似抑郁行为，而GRK2过表达则在正常小鼠中诱导出类似抑郁的行为。我们的研究确定海马体GRK2是CIA模型小鼠中与类风湿关节炎相关的类似抑郁行为的调节因子，提示了一个治疗靶点和潜在的治疗策略。
