2. Academic Validation
  3. Promoting AMPK/SR-A1-mediated clearance of HMGB1 attenuates chemotherapy-induced peripheral neuropathy

Promoting AMPK/SR-A1-mediated clearance of HMGB1 attenuates chemotherapy-induced peripheral neuropathy

  • Cell Commun Signal. 2023 May 4;21(1):99. doi: 10.1186/s12964-023-01100-9.
Xing Yang # 1,  Rumeng Jia # 1,  Fan Hu # 1,  Wen Fan # 1,  Tongtong Lin 1,  Xiaotao Zhang 2,  Chenjie Xu 3,  Shirong Ruan 1,  Chunyi Jiang 1,  Yan Li 4,  Cailong Pan 1,  Yang Yang 5,  Liang Hu 6,  Qi Chen 7,  Wen-Tao Liu 8
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, 211166, China.
  • 2 Department of Radiation Oncology, Qingdao Central Hospital, Qingdao, 266042, Shandong, China.
  • 3 Department of Anesthesiology and Pain, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, Jiangsu, China.
  • 4 Department of Oncology, Shandong Provincial Qianfoshan Hospital, The First Hospital Affiliated with Shandong First Medical University, Jinan, 250014, Shandong, China.
  • 5 Department of Anesthesiology, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, 210009, China. Jszlyyyy@163.com.
  • 6 Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, 211166, China. lianghu@njmu.edu.cn.
  • 7 Atherosclerosis Research Center, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, 211166, Jiangsu, China. qichen@njmu.edu.cn.
  • 8 Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, 211166, China. painresearch@njmu.edu.cn.
  • # Contributed equally.
PMID: 37143083 DOI: 10.1186/s12964-023-01100-9
Abstract

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a serious side effect of chemotherapy with poorly understood mechanisms and few treatments. High-mobility group box 1 (HMGB1)-induced neuroinflammation is the main cause of CIPN. Here, we aimed to illustrate the role of the macrophage scavenger receptor A1 (SR-A1) in HMGB1 clearance and CIPN resolution.

Methods: Oxaliplatin (L-OHP) was used to establish a CIPN model. Recombinant HMGB1 (rHMGB1) (his tag) was used to evaluate the phagocytosis of HMGB1 by macrophages.

Results: In the clinic, HMGB1 expression and MMP-9 activity were increased in the plasma of patients with CIPN. Plasma HMGB1 expression was positively correlated with the cumulative dose of L-OHP and the visual analog scale. In vitro, engulfment and degradation of rHMGB1 increased and inflammatory factor expression decreased after AMP-activated protein kinase (AMPK) activation. Neutralizing Antibodies, inhibitors, or knockout of SR-A1 abolished the effects of AMPK activation on rHMGB1 engulfment. In vivo, AMPK activation increased SR-A1 expression in the dorsal root ganglion, decreased plasma HMGB1 expression and MMP-9 activity, and attenuated CIPN, which was abolished by AMPK inhibition or SR-A1 knockout in the CIPN mice model.

Conclusion: Activation of the AMPK/SR-A1 axis alleviated CIPN by increasing macrophage-mediated HMGB1 engulfment and degradation. Therefore, promoting HMGB1 clearance may be a potential treatment strategy for CIPN. Video abstract.

Keywords

CIPN; Clearance; HMGB1; Macrophage; SR-A1.

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