New, Potent, Small Molecule Agonists of Tyrosine Kinase Receptors Improve Dry Eye Disease
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PROVIDER: PRJNA835818 | ENA |
REPOSITORIES: ENA
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Project description:Purpose: To investigate the mechanism for developing dry eye disease in the Pinkie mouse strain with a loss of function RXR mutation. Methods: Measures of dry eye disease were assessed in the cornea and conjunctiva. Expression profiling by single-cell RNA sequencing (scRNA-seq)was performed to compare gene expression in conjunctival immune cells. Conjunctival immune cells were immunophenotyped by flow cytometry and confocal microscopy. Activity of RXR ligand 9-cis retinoic acid (RA) was evaluated in cultured monocytes and T cells. Results: Compared to wild type (WT) C57BL/6, Pinkie has increased signs of dry eye disease, including corneal barrier disruption, conjunctival cornification and goblet cell loss, and corneal vascularization, opacification, and ulceration with aging. scRNA-seq of conjunctival immune cells identified T cells as the predominant IL-17 expressing population in both strains and there is a 4-fold increased percentage of T cells in Pinkie. Compared to WT, significantly increased expression of IL-17a and IL-17f in conventional T cells and IL-17f in T cells was found in Pinkie. Flow cytometry and immunostaining revealed an increased number of IL-17+ T cells in Pinkie. Tear concentration of the IL-17 inducer IL-23 is significantly higher in Pinkie. 9-cis RA treatment suppresses stimulated IL-17 production by T and stimulatory activity of monocyte supernatant on T cell IL-17 production. Compared to WT bone marrow chimeras, Pinkie chimeras have increased IL-17+ T cells in the conjunctiva after desiccating stress and anti-IL-17 treatment suppresses dry eye induced corneal MMP-9 production/activity and conjunctival goblet cell loss. Conclusion: These findings indicate that RXR suppresses generation of dry eye disease inducing T17 cells in the conjunctiva and identifies RXR as a potential therapeutic target in dry eye.
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