Vincristine-induced peripheral neuropathy is driven by canonical NLRP3 activation and IL-1β release

J Exp Med. 2021 May 3;218(5):e20201452. doi: 10.1084/jem.20201452.

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-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antirheumatic Agents / administration & dosage
  • Cisplatin / administration & dosage
  • Furans / administration & dosage
  • Humans
  • Hyperalgesia / chemically induced
  • Hyperalgesia / drug therapy
  • Hyperalgesia / genetics*
  • Indenes / administration & dosage
  • Inflammasomes / drug effects
  • Inflammasomes / genetics
  • Inflammasomes / metabolism
  • Interleukin 1 Receptor Antagonist Protein / administration & dosage
  • Interleukin-1beta / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics*
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Oxaliplatin / administration & dosage
  • Peripheral Nervous System Diseases / chemically induced
  • Peripheral Nervous System Diseases / drug therapy
  • Peripheral Nervous System Diseases / genetics*
  • Sulfonamides / administration & dosage
  • Vincristine
  • Xenograft Model Antitumor Assays / methods*

Substances

  • Antineoplastic Agents
  • Antirheumatic Agents
  • Furans
  • Indenes
  • Inflammasomes
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Sulfonamides
  • Oxaliplatin
  • Vincristine
  • N-(1,2,3,5,6,7-hexahydro-S-indacen-4-ylcarbamoyl)-4-(2-hydroxy-2-propanyl)-2-furansulfonamide
  • Cisplatin