Transient tear hyperosmolarity disrupts the neuroimmune homeostasis of the ocular surface and facilitates dry eye onset. Issue 2 (14th August 2020)

• Record Type: Journal Article
• Authors: Guzmán, Mauricio; Miglio, Maximiliano; Keitelman, Irene; Shiromizu, Carolina Maiumi; Sabbione, Florencia; Fuentes, Federico; Trevani, Analía S.; Giordano, Mirta N.; Galletti, Jeremías G.
• Is Part Of: Immunology. Volume 161:Issue 2(2020)
• Page Start: 148
• Page End: 161
• Publication Date: 2020-08-14
• Subjects: dry eye -- hyperosmolar stress -- ocular mucosal tolerance -- tear hyperosmolarity -- transient receptor potential vanilloid 1; Immunology -- Periodicals
• DOI: 10.1111/imm.13243
• Languages: English
• ISSNs: 0019-2805

Abstract

Abstract : Transient exposure to tear hyperosmolarity without desiccation is sufficient to disrupt the neuroimmune homeostasis of the murine ocular surface. This treatment elicits sub‐clinical dry eye findings, such as increased conjunctival dendritic cell recruitment and maturation, more CD4 + T‐cell activation, and changes in corneal nerve morphology and function. Also, the pathogenic CD4 + T‐cells induced by tear hyperosmolarity promote full dry eye onset in naïve recipients. Summary: 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 THO is sufficient to disrupt neuroimmune homeostasis of the ocular surface in mice, and thus reproduce many sub‐clinical DED findings. THO activated nuclear factor‐κB signalling 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 signalling 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 favoured 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.