2. Academic Validation
  3. TLR9 in satellite glial cells promotes paclitaxel-induced neuropathic pain by reducing Kir4.1 transcription through histone methylation activation

TLR9 in satellite glial cells promotes paclitaxel-induced neuropathic pain by reducing Kir4.1 transcription through histone methylation activation

  • Brain Behav Immun. 2025 Aug:128:65-82. doi: 10.1016/j.bbi.2025.03.037.
Qingtian Luo 1,  Jian Jiang 2,  Qing Zhu 3,  Sashuang Wang 4,  Yifei Wu 5,  Nan Li 4,  Xiyuan Ba 4,  Fengling Wu 4,  Xu Liu 4,  Yuhui Luo 4,  Donglin Xiong 4,  Lizu Xiao 4,  Xiang Liao 4,  Zhenhe Huang 6,  Zixian Chen 7,  Changyu Jiang 8
Affiliations

Affiliations

  • 1 Department of Gastroenterology and Endoscopy Center, Affiliated Nanshan Hospital of Shenzhen University, Shenzhen, Guangdong 518052, China; Department of Pain Medicine and Shenzhen Municipal Key Laboratory for Pain Medicine, Affiliated Nanshan Hospital of Shenzhen University, Shenzhen, Guangdong 518052, China.
  • 2 Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430022, China.
  • 3 Department of Pain Medicine, The Second Affiliated Hospital, Faculty of Medicine, The Chinese University of Hong Kong (Shenzhen), Shenzhen, Guangdong 518172, China.
  • 4 Department of Pain Medicine and Shenzhen Municipal Key Laboratory for Pain Medicine, Affiliated Nanshan Hospital of Shenzhen University, Shenzhen, Guangdong 518052, China.
  • 5 Department of Medical Neuroscience, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.
  • 6 Geriatric Medicine Department, Affiliated Nanshan Hospital of Shenzhen University, Shenzhen, Guangdong 518052, China.
  • 7 Department of Orthopedic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China. Electronic address: chen.zixian@zs-hospital.sh.cn.
  • 8 Department of Pain Medicine and Shenzhen Municipal Key Laboratory for Pain Medicine, Affiliated Nanshan Hospital of Shenzhen University, Shenzhen, Guangdong 518052, China. Electronic address: changyujiang@email.szu.edu.cn.
PMID: 40174869 DOI: 10.1016/j.bbi.2025.03.037
Abstract

Chemotherapy-induced neuropathic pain (CINP), commonly induced by paclitaxel (PTX), is a debilitating side effect that often leads to the discontinuation of Cancer treatment. Despite its significant impact on patients' quality of life, the mechanisms underlying CINP remain poorly understood. Recent studies have suggested that immune system activation, particularly through Toll-like Receptor 9 (TLR9), plays a crucial role in the development of neuropathic pain. In this study, we investigated the involvement of TLR9 in PTX-induced CINP, with a focus on satellite glial cells (SGCs) in the dorsal root ganglion (DRG). We found that TLR9 expression was significantly upregulated in SGCs following PTX treatment, and its activation contributed to the downregulation of Kir4.1 (potassium inwardly rectifying channel, subfamily J, member 10), a key Potassium Channel that regulates neuronal excitability. This process was mediated through histone methylation, involving the methyltransferase G9a and the NF-κB signaling pathway. Inhibition of TLR9 or knockdown of its expression alleviated PTX-induced pain behaviors while inhibiting G9a restored Kir4.1 function and reduced pain. These findings suggest that TLR9 and its downstream signaling pathways, including G9a-mediated histone modification, play a critical role in the development of CINP. Targeting TLR9 and histone methylation may provide novel therapeutic strategies for managing CINP and improving Cancer treatment outcomes.

Keywords

Dorsal root ganglion; Histone methylation; Kir4.1; Neuropathic pain; Satellite glial cells; Toll-like receptor 9.

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