Dry eye disease (DED) is a highly prevalent ocular surface disorder with neuroimmune pathophysiology. Tear hyperosmolarity (THO), a frequent finding in affected patients, is considered a key element in DED pathogenesis, yet existing animal models are based on subjecting the ocular surface to the more complex desiccating stress -decreased tear production and/or increased evaporation- instead of strict hyperosmolar stress. Here we characterized a murine model of THO that does not involve desiccating stress, thus allowing us to dissect the contribution of THO to DED. Our results showed that tear hyperosmolarity (THO) is sufficient to disrupt neuroimmune homeostasis of the ocular surface in mice, and thus reproduce many subclinical DED findings. THO activated nuclear factor-κB signaling in conjunctival epithelial cells and increased dendritic cell recruitment and maturation, leading to more activated (CD69+) and memory (CD62lo CD44hi) CD4+ T cells in the eye-draining lymph nodes. Ultimately, THO impaired the development of ocular mucosal tolerance to a topical surrogate antigen in a chain of events that included epithelial nuclear factor-κB signaling and activation of transient receptor potential vanilloid 1 as the probable hypertonicity sensor. Also, THO reduced the density of corneal intraepithelial nerves and terminals and sensitized the ocular surface to hypertonicity. Finally, the adoptive transfer of T cells from THO mice to naïve recipients under mild desiccating stress favored DED development, showing that THO is enough to trigger an actual pathogenic T cell response. Our results altogether demonstrate that THO is a critical initiating factor in DED development.
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