Macrophage-Derived Interleukin-1 is both Necessary and Sufficient for Vincristine-Induced Peripheral Neuropathy

Vincristine, an important chemotherapeutic used in various pediatric and adult malignancies, causes a dose-limiting sensorimotor neuropathy for which there is no effective treatment. Using a murine model of vincristine-induced neuropathy, we show that vincristine treatment was associated with an increase in the number of F4/80-positive macrophages in dorsal root ganglia and sciatic nerve, and caused activation of the NLRP3 inflammasome and subsequent release of interleukin-1ß from macrophages in vitro and in vivo.  Depletion of macrophages with liposomal clodronate prevented development of vincristine-induced neuropathy, while intraplantar delivery of vincristine-treated wild-type, but not NLRP3-/-, macrophages caused the development of unilateral mechanical allodynia. 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.