2. Academic Validation
  3. NET-Triggered NLRP3 Activation and IL18 Release Drive Oxaliplatin-Induced Peripheral Neuropathy

NET-Triggered NLRP3 Activation and IL18 Release Drive Oxaliplatin-Induced Peripheral Neuropathy

  • Cancer Immunol Res. 2022 Dec 2;10(12):1542-1558. doi: 10.1158/2326-6066.CIR-22-0197.
Tongtong Lin # 1,  Liang Hu # 1,  Fan Hu # 1,  Kun Li 1,  Chao-Yu Wang 1,  Li-Juan Zong 1,  Ya-Qian Zhao 1,  Xiaotao Zhang 2,  Yan Li 3,  Yang Yang 4,  Yu Wang 1,  Chun-Yi Jiang 1,  Xuefeng Wu 5,  Wen-Tao Liu 1
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, China.
  • 2 Department of Radiation Oncology, Qingdao Central Hospital, Qingdao, Shandong, China.
  • 3 Department of Oncology, Shandong Provincial Qianfoshan Hospital, The First Hospital Affiliated with Shandong First Medical University, Jinan, Shandong, China.
  • 4 The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, China.
  • 5 State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China.
  • # Contributed equally.
PMID: 36255412 DOI: 10.1158/2326-6066.CIR-22-0197
Abstract

Oxaliplatin is an antineoplastic agent frequently used in the treatment of gastrointestinal tumors. However, it causes dose-limiting sensorimotor neuropathy, referred to as oxaliplatin-induced peripheral neuropathy (OIPN), for which there is no effective treatment. Here, we report that the elevation of neutrophil extracellular traps (NET) is a pathologic change common to both Cancer patients treated with oxaliplatin and a murine model of OIPN. Mechanistically, we found that NETs trigger NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and the subsequent release of IL18 by macrophages, resulting in mechanical hyperalgesia. In NLRP3-deficient mice, the mechanical hyperalgesia characteristic of OIPN in our model was reduced. In addition, in the murine model, treatment with the IL18 decoy receptor IL18BP prevented the development of OIPN. We further showed that eicosapentaenoic acid (EPA) reduced NET formation by suppressing the LPS-TLR4-JNK pathway and thereby abolished NLRP3 inflammasome activation and the subsequent secretion of IL18, which markedly prevented oxaliplatin-induced mechanical hyperalgesia in mice. These results identify a role for NET-triggered NLRP3 activation and IL18 release in the development of OIPN and suggest that utilizing IL18BP and EPA could be effective treatments for OIPN.

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