Neutrophil extracellular traps as a unique target in the treatment of chemotherapy-induced peripheral neuropathyResearch in context
Chao-Yu Wang,
Tong-Tong Lin,
Liang Hu,
Chen-Jie Xu,
Fan Hu,
Li Wan,
Xing Yang,
Xue-Feng Wu,
Xiao-Tao Zhang,
Yan Li,
Hao-Yuan Yin,
Chun-Yi Jiang,
Hong-Liang Xin,
Wen-Tao Liu
Affiliations
Chao-Yu Wang
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, China
Tong-Tong Lin
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, China
Liang Hu
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, China
Chen-Jie Xu
Department of Anesthesiology and Pain, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
Fan Hu
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, China
Li Wan
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, China
Xing Yang
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, China
Xue-Feng Wu
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China
Xiao-Tao Zhang
Department of Oncology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, China; Department of Radiation Oncology, Qingdao Central Hospital, Qingdao, Shandong, China
Yan Li
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
Hao-Yuan Yin
Department of Pharmaceutics and Key Laboratory of Cardiovascular & Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing Jiangsu, China
Chun-Yi Jiang
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, China; Corresponding author.
Hong-Liang Xin
Department of Pharmaceutics and Key Laboratory of Cardiovascular & Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing Jiangsu, China; Corresponding author.
Wen-Tao Liu
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, China; Corresponding author.
Summary: 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 China 81870870, 81971047, 81773798, 82271252; Natural Science Foundation of Jiangsu Province BK20191253; Major Project of “Science and Technology Innovation Fund” of Nanjing Medical University 2017NJMUCX004; Key R&D Program (Social Development) Project of Jiangsu Province BE2019732; Nanjing Special Fund for Health Science and Technology Development YKK19170.
