Reduced RXRa signaling increases dry eye disease inducing gdT17 cells in the conjunctiva [Nanostring]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE192960 | GEO | 2022/01/04

REPOSITORIES: GEO