ABSTRACT
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-1ß 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.
Subject(s)
Hyperalgesia/genetics , Interleukin-1beta/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , Peripheral Nervous System Diseases/genetics , Xenograft Model Antitumor Assays/methods , Animals , Antineoplastic Agents/administration & dosage , Antirheumatic Agents/administration & dosage , Cisplatin/administration & dosage , Furans/administration & dosage , Humans , Hyperalgesia/chemically induced , Hyperalgesia/drug therapy , Indenes/administration & dosage , Inflammasomes/drug effects , Inflammasomes/genetics , Inflammasomes/metabolism , Interleukin 1 Receptor Antagonist Protein/administration & dosage , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, Knockout , Mice, SCID , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Oxaliplatin/administration & dosage , Peripheral Nervous System Diseases/chemically induced , Peripheral Nervous System Diseases/drug therapy , Sulfonamides/administration & dosage , VincristineABSTRACT
Pain is a fundamental feature of inflammation. The immune system plays a critical role in the activation of sensory neurons and there is increasing evidence of neuro-inflammatory mechanisms contributing to painful pathologies. The inflammasomes are signaling multiprotein complexes that are key components of the innate immune system. They are intimately involved in inflammatory responses and their activation leads to production of inflammatory cytokines that in turn can affect sensory neuron function. Accordingly, the contribution of inflammasome activation to pain signaling has attracted considerable attention in recent years. NLRP3 is the best characterized inflammasome and there is emerging evidence of its role in a variety of inflammatory pain conditions. In vitro and in vivo studies have reported the activation and upregulation of NLRP3 in painful conditions including gout and rheumatoid arthritis, while inhibition of NLRP3 function or expression can mediate analgesia. In this review, we discuss painful conditions in which NLRP3 inflammasome signaling has been pathophysiologically implicated, as well as NLRP3 inflammasome-mediated mechanisms and signaling pathways that may lead to the activation of sensory neurons.