Neuronal Interaction with the Extracellular Environment in the Models of CIPN

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.