Direct sensitizing and activating effects of interleukin 31 are restricted to a single, functionally and transcriptionally classified porcine DRG neuron subtype.

Interleukin-31 (IL-31) drives chronic pruritus in patients with dermatological and even certain systemic diseases. However, fast-onset anti-pruritic effects of blocking IL-31 receptors, for instance with nemolizumab in atopic dermatitis patients, are incompletely understood, in part due to ethical restrictions in humans and species differences to mice. Therefore, we used sensory neuron cultures from pig to investigate direct neuronal IL-31 effects. We first mapped functional characteristics of afferents encoding histamine itch in humans onto a recently established transcriptome-based DRG neuron taxonomy to identify pig pruriceptors. IL-31 acutely sensitized responses to repeated pruritogen and electrical stimulation only in these histamine- and capsaicin-responsive pruriceptors and also activated these afferents with silent nociceptor phenotype in vivo as validated by dermal axon-reflex erythema measurements. Thus, our data functionally and transcriptionally identifies the likely sensory neuron class underlying IL-31-driven chronic pruritus and opens a perspective for translational research on distinct neuronal classes differentially driving skin inflammation and clinical chronic pruritus via specific neuro-immune signaling patterns.