2. Academic Validation
  3. Neutrophil extracellular traps as a unique target in the treatment of chemotherapy-induced peripheral neuropathy

Neutrophil extracellular traps as a unique target in the treatment of chemotherapy-induced peripheral neuropathy

  • EBioMedicine. 2023 Mar 2;90:104499. doi: 10.1016/j.ebiom.2023.104499.
Chao-Yu Wang 1,  Tong-Tong Lin 1,  Liang Hu 1,  Chen-Jie Xu 2,  Fan Hu 1,  Li Wan 1,  Xing Yang 1,  Xue-Feng Wu 3,  Xiao-Tao Zhang 4,  Yan Li 5,  Hao-Yuan Yin 6,  Chun-Yi Jiang 7,  Hong-Liang Xin 8,  Wen-Tao Liu 9
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, China.
  • 2 Department of Anesthesiology and Pain, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
  • 3 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China.
  • 4 Department of Oncology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, China; Department of Radiation Oncology, Qingdao Central Hospital, Qingdao, Shandong, China.
  • 5 Department of Oncology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, China; Department of Oncology, Shandong Provincial Qianfoshan Hospital, The First Hospital Affiliated with Shandong First Medical University, Jinan, Shandong, China.
  • 6 Department of Pharmaceutics and Key Laboratory of Cardiovascular & Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing Jiangsu, China.
  • 7 Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, China. Electronic address: jcy@njmu.edu.cn.
  • 8 Department of Pharmaceutics and Key Laboratory of Cardiovascular & Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing Jiangsu, China. Electronic address: xhl@njmu.edu.cn.
  • 9 Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, China. Electronic address: painresearch@njmu.edu.cn.
PMID: 36870200 DOI: 10.1016/j.ebiom.2023.104499
Abstract

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a severe dose-limiting side effect of chemotherapy and remains a huge clinical challenge. Here, we explore the role of microcirculation hypoxia induced by neutrophil extracellular traps (NETs) in the development of CIPN and look for potential treatment.

Methods: The expression of NETs in plasma and dorsal root ganglion (DRG) are examined by ELISA, IHC, IF and Western blotting. IVIS Spectrum imaging and Laser Doppler Flow Metry are applied to explore the microcirculation hypoxia induced by NETs in the development of CIPN. Stroke Homing peptide (SHp)-guided deoxyribonuclease 1 (DNase1) is used to degrade NETs.

Findings: The level of NETs in patients received chemotherapy increases significantly. And NETs accumulate in the DRG and limbs in CIPN mice. It leads to disturbed microcirculation and ischemic status in limbs and sciatic nerves treated with oxaliplatin (L-OHP). Furthermore, targeting NETs with DNase1 significantly reduces the chemotherapy-induced mechanical hyperalgesia. The pharmacological or genetic inhibition on myeloperoxidase (MPO) or peptidyl arginine deiminase-4 (PAD4) dramatically improves microcirculation disturbance caused by L-OHP and prevents the development of CIPN in mice.

Interpretation: In addition to uncovering the role of NETs as a key element in the development of CIPN, our finding provides a potential therapeutic strategy that targeted degradation of NETs by SHp-guided DNase1 could be an effective treatment for CIPN.

Funding: This study was funded by the National Natural Science Foundation of China81870870, 81971047, 81773798, 82271252; Natural Science Foundation of Jiangsu ProvinceBK20191253; Major Project of "Science and Technology Innovation Fund" of Nanjing Medical University2017NJMUCX004; Key R&D Program (Social Development) Project of Jiangsu ProvinceBE2019732; Nanjing Special Fund for Health Science and Technology DevelopmentYKK19170.

Keywords

Chemotherapy-induced peripheral neuropathy; Microcirculatory disturbance; Neutrophil extracellular traps; SHp-DNase1.

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