Rewiring Atopic Dermatitis: Alarmin Cytokines at the Core of Barrier-Immune-Neuro-Microbiome Networks

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by barrier dysfunction, type 2 immune dysregulation, pruritus, and microbial dysbiosis. Increasing evidence has revealed that epithelial-derived alarmin cytokines-thymic stromal lymphopoietin (TSLP), interleukin (IL)-33, and IL-25-are central upstream regulators that integrate structural damage with immune activation. These alarmin cytokines are rapidly induced by barrier stress and function at the epithelial-immune interface to orchestrate dendritic cell conditioning, group 2 innate lymphoid cell (ILC2) activation, T helper (Th) 2 polarization, and inflammatory memory. In addition to canonical immune amplification, alarmins directly modulate epidermal cell differentiation, antimicrobial responses, and neuro-immune circuits, thereby contributing to chronic itch, microbial imbalance, and relapse. Although TSLP, IL-33, and IL-25 exhibit overlapping functions, they operate in a coordinated and context-dependent manner. TSLP is predominantly a master regulator of adaptive type 2 immunity, IL-33 serves as a rapid innate immune amplifier and neuronal sensitizer, and IL-25 reinforces IL-13-dominant inflammatory circuits and memory-like ILC2 responses. Clinical trials targeting individual alarmins have reported strong biological rationales but variable efficacy in individuals with established moderate-to-severe AD, underscoring pathway integration and disease-stage specificity. This review synthesizes current advances in alarmin biology, including their cellular sources, receptor signaling, and roles in barrier dysfunction, dysbiosis, and neuroimmune crosstalk, as well as emerging clinical data. Understanding the context-specific functions of epithelial alarmins may inform the development of precision therapeutic strategies and redefine AD as a dynamic epithelial-immune disorder driven by upstream stress signaling networks.