Direct sensitizing and activating effects of IL-31 are restricted to a single, functionally, and transcriptionally classified porcine dorsal root ganglion neuron subtype.

IL-31 drives chronic pruritus in patients with dermatological and even certain systemic diseases. However, the fast-onset antipruritic effects of blocking IL-31 receptors, for instance, with nemolizumab in patients with atopic dermatitis, are incompletely understood, in part owing to ethical restrictions in humans and species differences from mice. Therefore, we used sensory neuron cultures from pigs 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 dorsal root ganglion 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 a silent nociceptor phenotype in vivo as validated by dermal axon-reflex erythema measurements. Thus, our data functionally and transcriptionally identify the likely sensory neuron class underlying IL-31-driven chronic pruritus and open a perspective for translational research on distinct neuronal classes differentially driving skin inflammation and clinical chronic pruritus through specific neuroimmune signaling patterns.