Topical rewetting restores the autoimmune-damaged corneal stroma

Corneal wetting is the most common treatment for relieving the signs and symptoms of dry eye and is considered to be largely palliative without therapeutic value. Here, we challenge this notion by demonstrating that wetting the desiccated cornea of an aqueous-deficient mouse model with the simplest form of wetting agent, phosphate buffered saline, is sufficient to rescue the severely disrupted collagen-rich architecture of the stroma, the largest corneal compartment that is essential to transparency and vision. Using transmission electron microscopy, we show the profound restoration of stromal architecture including a significant reduction in interfibrillar distance indicative stromal edema in response to 3X daily corneal rewetting using PBS. Using single cell transcriptomics, we show that stromal keratocytes responsible for maintaining stromal integrity are converted from an inflammatory state into a unique reparative cell state by rewetting alone, thus revealing the extensive plasticity of these cells and the regenerative function of rewetting the surface. We further show that the generation of a reparative phenotype is due, in part, to disruption of IL1β-MAPK signaling. Thus, our study uncovers the regenerative potential of topical wetting in dry eye and represents a paradigm shift in our understanding of its therapeutic impact.