Papers of the Week

Epidermal hyperinnervation is a critical feature of pruritus during skin inflammation. However, the mechanisms underlying epidermal hyperinnervation are unclear. This study investigates the role of the transcription factor EGR1 in epidermal innervation by utilizing wild-type (Egr1) and Egr1-null (Egr1) mice topically applied dust mite extract from Dermatophagoides farinae (DfE). Our findings revealed that Egr1 mice exhibited reduced scratching behaviors and decreased density of epidermal innervation compared to Egr1 mice. Furthermore, we identified artemin (ARTN), a neurotrophic factor, as an EGR1 target responsible for DfE-induced hyperinnervation. It has been demonstrated that DfE stimulates toll-like receptors (TLRs) in keratinocytes. To elucidate the cellular mechanism, we stimulated keratinocytes with Pam3CSK4, a toll-like receptor (TLR) 1/2 ligand. Pam3CSK4 triggered a TLR1/2-mediated signaling cascade involving IRAK4, IKK, MAPKs, ELK1, EGR1, and ARTN, leading to increased neurite outgrowth and neuronal migration. Additionally, increased expression of EGR1 and ARTN was observed in the skin tissues of patients with atopic dermatitis. These findings highlight the significance of the EGR1-ARTN axis in keratinocytes, promoting the process of epidermal innervation and suggesting it as a potential therapeutic target for alleviating itch and pain associated with house dust mite-induced skin inflammation.