Starts:

Tuesday, September 20th
4:30pm-6:00pm EDT

Category:

Topical Workshop

Tracks:

Basic Science

Room

717 A/B

Chemotherapy-induced Peripheral Neuropathy: Pathophysiology and Mechanism-based Treatment

CIPN is common following chemotherapy and is clinically poorly managed, thus understanding the underlying mechanisms could lead to more effective treatment. Nav1.6 but not Nav1.7 is important for the maintenance of vincristine-induced pain (VIP) in mice, while live imaging shows that paclitaxel increases trafficking of Nav1.7 to distal ends of sensory neuron axons, which is significantly increased by the concomitant treatment with inflammatory mediators. VIP in mice is driven by activation of the NLRP3 inflammasome and subsequent release of interleukin-1β from macrophages, and is significantly reduced in mice lacking NLRP3 signaling pathway components, or after treatment with the NLRP3 inhibitor MCC950. Additionally, the IL-1 receptor antagonist anakinra prevented the development of VIP without adversely affecting chemotherapy efficacy in patient-derived medulloblastoma xenograph models. Chronic treatment of Drosophila larvae with paclitaxel caused altered branching and degeneration of nociceptive neurons, reduced thermal nociceptive responses, and activated resident macrophage-like cells, suggesting a conserved neuron-immune interaction contributing to the CIPN pathology Live imaging and superresolution approaches show alterations in endosome-mediated trafficking of integrins, and nociceptive neuron-specific overexpression of integrins conferred a protective effect. This workshop will discuss the interplay between chemotherapy-induced peripheral neuropathy and pain (CIPN) and inflammation using innovative conceptual and methodological approaches.

Presentations

Time
4:30pm EDT6:00pm EDT

Insights into the Contribution of Nav Channels to CIPN

Tracks: Basic Science
Categories: Topical Workshop

The microtubule-targeting chemotherapeutic agents paclitaxel (PTX, stabilizer) and vincristine (Vin, destabilizer) produce painful peripheral neuropathy (CIPN), but the underlying mechanisms are not well understood. We now show that Vin-treated mice develop allodynia not accompanied by nerve damage . We also showed an up-regulation of TTX-S Na+ current in medium but not small neurons, which is mediated by Nav1.6, because mechanical allodynia was attenuated in conditional Nav1.6 KO, but not Nav1.7 KO mice. By contrast, ptx increases NaV1.7 expression in sensory neurons. Using our recently developed optical pulse-chase axonal long distance live-imaging approach , we demonstrated concentration- and time-dependent increase in vesicular trafficking and membrane localization of NaV1.7 in sensory axons. Concurrent treatment with inflammatory mediators to mimic the inflammatory condition accompanying chemotherapy, both NaV1.7 surface levels and vesicular transport are increased. Overall, our results show that Vin and PTX treatment increases levels of functional endogenous NaV1.6 and NaV1.7 channels in DRG neurons in a drug and cell-type dependent manner, and show that PTX enhances trafficking and surface distribution of NaV1.7 in sensory axons, which are augmented in the presence of an inflammatory milieu.

4:30pm EDT6:00pm EDT

Macrophage-derived Interleukin-1ß is both Necessary and Sufficient for Vincristine-induced Peripheral Neuropathy

Tracks: Basic Science
Categories: Topical Workshop
Presented By: Dr. Irina Vetter

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.

4:30pm EDT6:00pm EDT

Neuronal Interaction with the Extracellular Environment in the Models of CIPN

Tracks: Basic Science
Categories: Topical Workshop
Presented By: Dr. Grace J. Shin

Peripheral sensory neurons have highly dynamic terminals embedded in the skin layer and interact with local immune cells for their structural integrity and function. How this intricate balance is achieved in the dynamic environment and how this process goes awry under cellular stress are largely unknown. We examined mechanisms underlying CIPN and identified conserved pathways in a Drosophila model and primary sensory neurons isolated from adult mouse. We found that nociceptive neuron-specific overexpression of integrins, which are known to support neuronal maintenance in several systems, conferred protection from paclitaxel-induced cellular and behavioral phenotypes. Live imaging and superresolution approaches provide evidence of paclitaxel-induced cellular changes consistent with alterations in endosome-mediated trafficking of integrins. In mouse primary DRG neuron cultures, we show that augmenting a human integrin β-subunit 1 also prevented degeneration following paclitaxel treatment and provide further evidence that paclitaxel disrupts recycling in sensory neurons. Altogether, our study supports conserved mechanisms of paclitaxel-induced perturbation of integrin trafficking and a therapeutic potential of restoring neuronal interactions with the extracellular environment to antagonize paclitaxel-induced toxicity in sensory neurons. Leveraging from this work, our recent investigation focuses on the pathological mechanisms of surrounding immune cells and their interactions with nociceptive neurons in CIPN models.

Presenters

Dr. Irina Vetter

Director of Pain Research
The University of Queensland

Dr. Sulayman D. Dib-Hajj

Senior Research Scientist
Yale Sch Med and VACT Healthcare System/Neuroscience Research Center

Dr. Grace J. Shin

Associate Research Scientist
Columbia University