1. Academic Validation
  2. 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. [email protected].
  • 6 Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, 211166, China. [email protected].
  • 7 Atherosclerosis Research Center, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, 211166, Jiangsu, China. [email protected].
  • 8 Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, 211166, China. [email protected].
  • # Contributed equally.
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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