Transient tear hyperosmolarity disrupts the neuroimmune homeostasis of the ocular surface and facilitates dry eye onset

GUZMÁN, MAURICIO; MIGLIO, MAXIMILIANO; KEITELMAN, IRENE; SHIROMIZU, CAROLINA MAIUMI; SABBIONE, FLORENCIA; FUENTES, FEDERICO; TREVANI, ANALÍA S.; GIORDANO, MIRTA N.; GALLETTI, JEREMÍAS G.

IMMUNOLOGY

WILEY-BLACKWELL PUBLISHING, INC

Año: 2020

0019-2805

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