The neuro-immune-epithelial axis in dry eye: From pathogenic crosstalk to neuromodulatory therapies

Dry eye disease (DED) is commonly described through tear-film instability, tear deficiency, evaporative stress, and ocular surface inflammation. These models remain central to diagnosis and treatment, but they do not fully explain symptom-sign discordance, persistent discomfort after surface-directed therapy, epithelial disease with reduced corneal sensation, or variable treatment responses. In this structured narrative review, we synthesize DED-specific, phenotype-specific, adjacent ocular surface, and translational evidence relevant to a bidirectional neuro-immune-epithelial axis involving corneal sensory nerves, trigeminal-parasympathetic reflexes, epithelial and goblet-cell barrier function, and immune-cell activation. Available sensory evidence indicates that corneal sensory abnormalities in DED are heterogeneous: mechanical esthesiometry more often shows reduced sensitivity, whereas non-contact esthesiometry and pain-enriched cohorts may show hypersensitivity or mixed findings. In vivo confocal microscopy (IVCM) studies suggest concurrent changes in corneal nerve morphology and epithelial immune-cell density, but validated thresholds are not sufficient to define a routine neural DED subtype. Neural dysfunction is therefore considered a phenotype-dependent contributor or amplifier, rather than a universal nerve-first mechanism. Treatment implications are discussed according to evidence strength and directness. Varenicline nasal spray and acoltremon engage reflex or sensory tear pathways where approved; motugivatrep illustrates region-specific TRPV1 translation in Japan; diquafosol and rebamipide are epithelial/mucin-supportive therapies with indirect axis relevance; and cenegermin remains primarily a neurotrophic keratitis therapy with restricted relevance to selected DED phenotypes. Neuropeptide-specific targets, availability-limited device stimulation, and direct nerve-regenerative claims for photobiomodulation remain preliminary. This framework may support mechanism-based stratification and rational adjunctive therapy without replacing established DED classifications.