2. Academic Validation
  3. Geranyl hydroquinone alleviates rheumatoid arthritis-associated pain by suppressing neutrophil accumulation, N1 polarization and ROS production in mice

Geranyl hydroquinone alleviates rheumatoid arthritis-associated pain by suppressing neutrophil accumulation, N1 polarization and ROS production in mice

  • Redox Biol. 2025 Mar 18:82:103603. doi: 10.1016/j.redox.2025.103603.
Sen Huang 1,  Yuxin Xie 2,  Zhaochun Zhan 3,  Fengdong Liu 2,  Peiyang Liu 4,  Fei Xu 2,  Tingting Xu 2,  Zhenning Fang 5,  Zhiqiang Chen 6,  Qingjian Han 7,  Ligang Jie 8,  Rougang Xie 4,  Hongfei Zhang 9,  Shiyuan Xu 9,  Yiwen Zhang 10,  Kai Mo 11,  Xin Luo 12
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China; Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
  • 2 Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
  • 3 Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China; Department of Anesthesiology, Shunde Hospital, Southern Medical University, Foshan, 528300, China.
  • 4 Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China.
  • 5 Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China.
  • 6 Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China; Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China; Department of Anesthesiology, Shunde Hospital, Southern Medical University, Foshan, 528300, China.
  • 7 State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, 200032, China.
  • 8 Department of Rheumatology and Clinical Immunology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China.
  • 9 Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China; Institute of Perioperative Medicine and Organ Protection, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China.
  • 10 Department of Anesthesiology, Shunde Hospital, Southern Medical University, Foshan, 528300, China. Electronic address: ssss047@163.com.
  • 11 Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China; Institute of Perioperative Medicine and Organ Protection, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China. Electronic address: mokai303@163.com.
  • 12 Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China; Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China; Department of Anesthesiology, Shunde Hospital, Southern Medical University, Foshan, 528300, China; Institute of Perioperative Medicine and Organ Protection, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China. Electronic address: xin.luo21@hotmail.com.
PMID: 40147153 DOI: 10.1016/j.redox.2025.103603
Abstract

Pain hypersensitivity is a hallmark of rheumatoid arthritis (RA); however, the underlying mechanisms and effective therapies remain largely undefined. Emerging studies suggest that neutrophils play a significant role in the pathology of RA, yet their involvement in RA-associated pain is still unclear. The present study investigates whether neutrophil activity contributes to pain pathogenesis in RA. Our flow cytometry analysis reveals that the accumulation and N1 polarization (indicated by the ratio of CD45+CD66b+CD95+ subset) of neutrophils occur in synovial fluid samples from RA patients, positively correlating with pain scores. In the collagen-induced rheumatoid arthritis (CIA) model, mice demonstrate neutrophil accumulation, N1 polarization (indicated by the ratio of CD45+Ly-6G+CD95+ subset), and Reactive Oxygen Species (ROS) production in affected paw tissues. Geranyl hydroquinone (GHQ), a natural meroterpenoid with antioxidative properties, reverses N1 polarization and ROS production in synovial neutrophils from RA patients in vitro. Moreover, a 10-day oral administration of GHQ alleviates pain hypersensitivity and reduces neutrophil accumulation, N1 polarization, and ROS production in CIA mice. Notably, GHQ treatment reverses TNF-α-evoked ROS production in neutrophils in vitro through downregulating gene expression associated with the ROS pathway. Further, liquid chromatography-tandem mass spectrometry and biochemical analyses indicate that GHQ binds to microsomal Glutathione S-transferase 3 (MGST3) in neutrophils. In vitro and in vivo evidence demonstrates that the RA-specific analgesic and antioxidative effects of GHQ require MGST3. Lastly, GHQ administration exhibits superior therapeutic effects compared to methotrexate, a first-line disease-modifying antirheumatic drug, in CIA mice. Collectively, our findings indicate that neutrophil accumulation, N1 polarization and ROS production contribute to RA-associated pain, suggesting that targeting these pathways, such as with GHQ, could be a viable strategy for RA treatment.

Keywords

Microsomal glutathione S-Transferase 3; Neutrophils; Pain; Reactive oxygen species; Rheumatoid arthritis.

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