Neuroimmune pharmacotherapy across the skin-brain axis: mechanisms, therapeutic targets, and AI-enabled precision approaches.

Abstract

The skin-brain axis is a bidirectional neuroimmune network linking cutaneous inflammation with central neuroinflammation, stress signaling, and behavioral disturbances. This review summarizes the mechanisms underlying skin-brain communication and evaluates current and emerging pharmacological strategies targeting this axis in inflammatory skin disorders. We synthesized contemporary experimental, translational, and clinical evidence on neuroimmune signaling across the skin-brain axis, with emphasis on sensory neuron-immune cell interactions, neurogenic inflammation, glial activation, pharmacological targets, biomarkers, disease models, and artificial intelligence (AI)-enabled precision approaches. Current evidence suggests that chronic cutaneous inflammation may promote central neuroimmune activation through neuropeptides, cytokines, and stress-responsive pathways. Central stress signaling can, in turn, exacerbate skin disease. Substance P, calcitonin gene-related peptide, transient receptor potential channels, microglia, and astrocytes emerge as key mediators linking peripheral inflammation to altered neuroplasticity and affective symptoms. Therapeutic approaches including biologics, Janus kinase and phosphodiesterase-4 inhibitors, neuromodulators, and transient receptor potential antagonists show promise in reducing pruritus and neuropsychiatric comorbidity. However, pharmacodynamic variability and incomplete response remain important limitations. Biomarkers, multi-omic profiling, and advanced preclinical models may improve translational evaluation, while AI tools may support biomarker discovery, digital phenotyping, and individualized treatment selection. The skin-brain axis represents a pharmacologically actionable framework for inflammatory skin disease. Integrated strategies addressing peripheral inflammation, central neuroimmune dysregulation, and psychosocial burden may improve precision pharmacotherapy and clinical outcomes.