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-1β 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.
Vincristine-induced peripheral neuropathy is driven by canonical NLRP3 activation and IL-1β release
Disclosures: K. Schroder reported "other" from Inflazome Ltd outside the submitted work; in addition, K. Schroder had a patent to PCT/EP2017/053498 licensed (Inflazome Ltd), a patent to PCT/IB2017/053059 licensed (Inflazome Ltd), and a patent to PCT/AU2016/050103 licensed (Inflazome Ltd); served on the Scientific Advisory Board of Inflazome in 2016-2017; and serves as a consultant to Quench Bio, USA and Novartis, Switzerland. No other disclosures were reported.
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Hana Starobova, Mercedes Monteleone, Christelle Adolphe, Lena Batoon, Cheyenne J. Sandrock, Bryan Tay, Jennifer R. Deuis, Alexandra V. Smith, Alexander Mueller, Evelyn Israel Nadar, Grace Pamo Lawrence, Amanda Mayor, Elissa Tolson, Jean-Pierre Levesque, Allison R. Pettit, Brandon J. Wainwright, Kate Schroder, Irina Vetter; Vincristine-induced peripheral neuropathy is driven by canonical NLRP3 activation and IL-1β release. J Exp Med 3 May 2021; 218 (5): e20201452. doi: https://doi.org/10.1084/jem.20201452
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