The Neuroimmune Axis in Atopic Dermatitis: From Pathogenic Mechanisms to Targeted Neuroimmunotherapy.

Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease in which intense pruritus and eczematous lesions arise from tightly coupled disturbances of the nervous and immune systems. Emerging evidence indicates that a dysregulated neuroimmune axis-as reflected by peripheral neuronal sensitization, epidermal barrier dysfunction, and central itch processing-plays a central role in disease onset, persistence, and clinical heterogeneity. In this review, we synthesize current knowledge on the neuroimmune mechanisms that drive AD, focusing on how cytokines such as IL-31, IL-4/IL-13, TSLP and IL-33, together with neuropeptides including substance P, CGRP and VIP, establish self-reinforcing itch-scratch and inflammation loops at the level of the skin and the central nervous system. We then highlight recent multi-omics and systems biology approaches, including single-cell and spatial transcriptomics, neuroimaging, and microbiome profiling, that have reshaped the understanding of neuroimmune "neighbourhoods" and the gut-skin-brain axis in AD. Building on these mechanistic insights, we summarize key neuroimmune biomarkers-such as NGF, IL-31, TARC/CCL17, S100 proteins, barrier-related lipids, neurofunctional readouts from fMRI, and microbial signatures-and discuss their potential for improving diagnosis, patient stratification, and treatment monitoring within a precision medicine framework. Finally, we review established and emerging neuroimmune-targeted therapies, including IL-4/IL-13 and IL-31 pathway inhibitors, JAK inhibitors, OX40/OX40L-directed biologics, TRP and NK1R antagonists, phototherapy, and microbiome-based interventions, with a particular emphasis on biomarker-guided sequencing and combination strategies. Overall, we propose that positioning the neuroimmune axis at the core of AD pathogenesis provides a conceptual basis for developing stratified, durable, and patient-centred neuroimmunotherapy, while also outlining the remaining challenges regarding clinical validation of biomarkers, long-term safety, accessibility, and implementation across diverse patient populations.