In the sciatic nerve of PBS-treated C57BL/6J mice, we observed a small number of F4/80 + cells consistent with levels expected in healthy tissue (94.5 ± 12.2 cells/ mm 2 n = 7 Fig. In light of recent evidence suggesting a significant neuro-inflammatory component of VIPN ( Montague et al., 2018 Old et al., 2014 Starobova et al., 2019a) and observations that the longest axons are affected first ( Wang et al., 2000), we sought to confirm the previously reported ( Old et al., 2014) vincristine-induced infiltration of F4/80 + (pan-macrophage marker) cells into the sciatic nerve, which harbors some of the longest sensory axons innervating the plantar hind paw. 1 B and Table S1) however, vincristine did not induce changes in weight gain, general well being, gross motor performance, or heat PWTs ( Fig. In addition to mechanical allodynia, gait abnormalities were also apparent in animals treated with vincristine (10 µg i.pl. Specifically, as previously described, systemic and local treatment with vincristine (0.5 mg/kg i.p., 10 doses/12 d or 10 µg i.pl., 6 doses/12 d) elicited pronounced mechanical allodynia as evidenced by a significant decrease in mechanical paw withdrawal thresholds (PWTs Fig. or intraplantar (i.pl.) administration of vincristine ( Old et al., 2014 Starobova et al., 2019a Uçeyler et al., 2006). These symptoms are recapitulated in murine models based on i.p. Patients treated with vincristine develop sensory disturbances, such as hyperesthesia or altered responses to light touch and pinprick, as well as motoric disturbances, including altered gait and foot drop syndrome ( Kautio et al., 2011).
However, the signaling pathways leading to cytokine release from these infiltrating peripheral macrophages, as well as the contributions of these mechanisms to the development of vincristine-induced mechanical allodynia, are unknown. Indeed, a causative contribution of infiltrating peripheral macrophages was confirmed in CX 3CR 1- and CCR 2-deficient mice, which develop less mechanical allodynia after treatment with vincristine ( Montague et al., 2018 Old et al., 2014). Vincristine, in particular, induces a striking upregulation of inflammatory genes in dorsal root ganglia (DRG), and release of pro-inflammatory cytokines and chemokines, including IL-1β, TNFα, IL-6, and CCL2, is implicated in the development of VIPN ( Kiguchi et al., 2009 Starobova et al., 2019b). Although vincristine targets microtubules, and impaired retrograde and anterograde transport has been suggested as one mechanism leading to altered sensory neuron function, there is growing evidence that chemotherapy-induced neuropathy caused by a diverse range of agents incorporates significant neuro-inflammatory components ( Montague et al., 2018 Old et al., 2014 Starobova et al., 2019b). The exact pathophysiological mechanisms underlying VIPN remain unclear, which has hampered the development of effective treatment strategies that could either prevent or control the symptoms of VIPN. 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. 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. 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. 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.
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.