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G-protein coupled receptor kinase 2 mediates rheumatoid arthritis-induced depression-like behaviors via the hippocampal CRHR1 signaling pathway

Acta Pharmacologica Sinica (2025)Cite this article

Abstract

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−1·d−1, 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.

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Fig. 1: Depression-like behaviors in CIA mice.
Fig. 2: Hippocampal inflammation is increased in CIA mice.
Fig. 3: Depression-like behaviors are associated with downregulation of the CRHR1/cAMP/CREB/BDNF signaling pathway in CIA mice.
Fig. 4: GRK2 expression levels and interaction with CRHR1 in CIA mice.
Fig. 5: Hippocampal GRK2 knockdown reduces depression-like behaviors in CIA mice.
Fig. 6: Overexpression of hippocampal GRK2 induces depression-like phenotype in naive mice.
Fig. 7: Reduced CIA-associated depression-like behaviors following CP-25 treatment.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (grants 82173824, 82101311, 82403663), Natural Science Foundation of Anhui Educational Committee (2024AH050721, 2024AH050776), Research Foundation of Anhui Medical University (2020xkj014, 2023xkj013), Basic and Clinical Collaborative Research Enhancement Program of Hefei First People’s Hospital (9221022201), Anhui Province Excellent Research and Innovation Team Project (2024AH010013), Anhui Provincial Natural Science Foundation (2308085MH311), and the Key Projects of Natural Science Research of Anhui Colleges and Universities (2023AH050666).

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  1. These authors contributed equally: Qian Meng, Meng-hui Guo, Rui Zhang

Authors and Affiliations

  1. 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

    Qian Meng, Meng-hui Guo, Rui Zhang, Jing Wei, Qian Chen, Xue-chun Zhao, Cai-qi Xu, Yao-yao Wu, Jia-jie Kuai, Jie-min Zhao, Yu-jing Wu, Chong-huan Ye & Wei Wei

  2. CAS Key Laboratory of Brain Function and Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China

    Hong-rui Wei, Xia Zhu, Yan Jin & Zhi Zhang

  3. Department of Anatomy, School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China

    Zhi Zhang

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Contributions

QM, ZZ and WW contribute to conceptualization; QM and WW contribute to funding acquisition; QM, MHG, JW, XCZ, QC, CQX, YYW and JJK contribute to investigation; QM, MHG, RZ, JW and QC contribute to methodology; QM, MHG and RZ contribute to project administration; QM contributes to resources; QM, ZZ and WW contribute to supervision; QM, MHG, RZ, JW, XCZ, QC, CQX and YYW contribute to validation; MHG and JW contribute to visualization; MHG and XCZ contribute to formal analysis; QM, RZ, JMZ, YJW, HRW, CHY, XZ, YJ, ZZ and WW contribute to writing & editing.

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Correspondence to Qian Meng, Zhi Zhang or Wei Wei.

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Meng, Q., Guo, Mh., Zhang, R. et al. G-protein coupled receptor kinase 2 mediates rheumatoid arthritis-induced depression-like behaviors via the hippocampal CRHR1 signaling pathway. Acta Pharmacol Sin (2025). https://doi.org/10.1038/s41401-025-01621-8

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