期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 218, 期 5, 页码 -出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20201452
关键词
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资金
- University of Queensland International Scholarship
- Australian Government Research Training Program scholarships
- National Health and Medical Research Council [1163924, 1122240, 1186835, 1141131, 1162503, 1136130, 1139961]
- Discovery Early Career Researcher Award [DE200101300]
- Kids' Cancer Project
- Mater Foundation
- Australian Research Council [DE200101300] Funding Source: Australian Research Council
- National Health and Medical Research Council of Australia [1163924, 1139961, 1136130, 1162503, 1122240, 1186835] Funding Source: NHMRC
The study found that vincristine-induced peripheral neuropathy is driven by activation of the NLRP3 inflammasome and release of interleukin-1 beta. Treatment with NLRP3 inhibitor or IL-1 receptor antagonist could effectively reduce mechanical allodynia and gait disturbances. Repurposing anakinra may be an effective co-treatment strategy to prevent vincristine-induced peripheral neuropathy.
Vincristine is an important component of many regimens used for pediatric and adult malignancies, but it causes a dose-limiting sensorimotor neuropathy for which there is no effective treatment. This study aimed to delineate the neuro-inflammatory mechanisms contributing to the development of mechanical allodynia and gait disturbances in a murine model of vincristine-induced neuropathy, as well as to identify novel treatment approaches. Here, we show that vincristine-induced peripheral neuropathy is driven by activation of the NLRP3 inflammasome and subsequent release of interleukin-1 beta from macrophages, with mechanical allodynia and gait disturbances significantly reduced in knockout mice lacking NLRP3 signaling pathway components, or after treatment with the NLRP3 inhibitor MCC950. Moreover, treatment with the IL-1 receptor antagonist anakinra prevented the development of vincristine-induced neuropathy without adversely affecting chemotherapy efficacy or tumor progression in patient-derived medulloblastoma xenograph models. These results detail the neuro-inflammatory mechanisms leading to vincristine-induced peripheral neuropathy and suggest that repurposing anakinra may be an effective co-treatment strategy to prevent vincristine-induced peripheral neuropathy.
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