Neuronal BST2: A Pruritic Mediator alongside Protease-Activated Receptor 2 in the IL-27–Driven Itch Pathway

Abstract

Chronic itch is a common and complex symptom often associated with skin diseases like atopic dermatitis (AD). Although IL-27 is linked to AD, its role and clinical significance in itch remain undefined. We sought to investigate IL-27 function in itch using tissue specific-transgenic mice, various itch models, behaviour scoring, RNA-seq, and cytokine/kinase array. Our findings show that IL-27 receptors were overexpressed in human AD skin. Intradermal IL-27 injection failed to directly induce itch in mice, but upregulated skin PAR2 transcripts, a key factor in itch and AD. IL-27 activated human keratinocytes, increasing PAR2 transcription and activity. Co-injection of SLIGRL (PAR2 agonist) and IL-27 in mice heightened PAR2-mediated itch. Additionally, IL-27 boosted BST2 transcription in sensory neurons and keratinocytes. BST2 was upregulated in AD skin, and its injection in mice induced itch-like response. BST2 colocalized with sensory nerve branches in AD skin from both human and murine models. Sensory neurons released BST2, and mice with sensory neuron-specific BST2 knockout displayed reduced itch responses. Overall, this study provides evidence that skin IL-27/PAR2 and neuronal IL27/BST2 axes are implicated in cutaneous inflammation and pruritus. The discovery of neuronal BST2 in pruritus shed light on BST2 in the itch cascade.