IL-17 Producing Lymphocytes Cause Dry Eye and Corneal Disease With Aging in RXRα Mutant Mouse
PurposeTo investigate IL-17 related mechanisms for developing dry eye disease in the Pinkie mouse strain with a loss of function RXRα mutation.MethodsMeasures of dry eye disease were assessed in the cornea and conjunctiva. Expression profiling was performed by single-cell RNA sequencing (scRNA-seq)...
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| Format: | Article |
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Frontiers Media S.A.
2022-03-01
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| Series: | Frontiers in Medicine |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmed.2022.849990/full |
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| author | Jehan Alam Ghasem Yazdanpanah Rinki Ratnapriya Nicholas Borcherding Cintia S. de Paiva DeQuan Li Rodrigo Guimaraes de Souza Rodrigo Guimaraes de Souza Zhiyuan Yu Stephen C. Pflugfelder |
| author_facet | Jehan Alam Ghasem Yazdanpanah Rinki Ratnapriya Nicholas Borcherding Cintia S. de Paiva DeQuan Li Rodrigo Guimaraes de Souza Rodrigo Guimaraes de Souza Zhiyuan Yu Stephen C. Pflugfelder |
| author_sort | Jehan Alam |
| collection | DOAJ |
| description | PurposeTo investigate IL-17 related mechanisms for developing dry eye disease in the Pinkie mouse strain with a loss of function RXRα mutation.MethodsMeasures of dry eye disease were assessed in the cornea and conjunctiva. Expression profiling was performed by single-cell RNA sequencing (scRNA-seq) to compare gene expression in conjunctival immune cells. Conjunctival immune cells were immunophenotyped by flow cytometry and confocal microscopy. The activity of RXRα ligand 9-cis retinoic acid (RA) was evaluated in cultured monocytes and γδ T cells.ResultsCompared to wild type (WT) C57BL/6, Pinkie has increased signs of dry eye disease, including decreased tear volume, corneal barrier disruption, corneal/conjunctival cornification and goblet cell loss, and corneal vascularization, opacification, and ulceration with aging. ScRNA-seq of conjunctival immune cells identified γδ T cells as the predominant IL-17 expressing population in both strains and there is a 4-fold increased percentage of γδ T cells in Pinkie. Compared to WT, IL-17a, and IL-17f significantly increased in Pinkie with conventional T cells and γδ T cells as the major producers. Flow cytometry revealed an increased number of IL-17+ γδ 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 γδ T and stimulatory activity of monocyte supernatant on γδ T cell IL-17 production. Compared to WT bone marrow chimeras, Pinkie chimeras have increased IL-17+ γδ 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.ConclusionThese findings indicate that RXRα suppresses generation of dry eye disease-inducing IL-17 producing lymphocytes s in the conjunctiva and identifies RXRα as a potential therapeutic target in dry eye. |
| first_indexed | 2024-04-12T22:52:09Z |
| format | Article |
| id | doaj.art-29afba3f78fa49938e0e6e66b5c929a5 |
| institution | Directory Open Access Journal |
| issn | 2296-858X |
| language | English |
| last_indexed | 2024-04-12T22:52:09Z |
| publishDate | 2022-03-01 |
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| series | Frontiers in Medicine |
| spelling | doaj.art-29afba3f78fa49938e0e6e66b5c929a52022-12-22T03:13:19ZengFrontiers Media S.A.Frontiers in Medicine2296-858X2022-03-01910.3389/fmed.2022.849990849990IL-17 Producing Lymphocytes Cause Dry Eye and Corneal Disease With Aging in RXRα Mutant MouseJehan Alam0Ghasem Yazdanpanah1Rinki Ratnapriya2Nicholas Borcherding3Cintia S. de Paiva4DeQuan Li5Rodrigo Guimaraes de Souza6Rodrigo Guimaraes de Souza7Zhiyuan Yu8Stephen C. Pflugfelder9Department of Ophthalmology, Ocular Surface Center, Baylor College of Medicine, Houston, TX, United StatesDepartment of Ophthalmology, Ocular Surface Center, Baylor College of Medicine, Houston, TX, United StatesDepartment of Ophthalmology, Baylor College of Medicine, Houston, TX, United StatesDepartment of Pathology, Washington University School of Medicine, St. Louis, MO, United StatesDepartment of Ophthalmology, Ocular Surface Center, Baylor College of Medicine, Houston, TX, United StatesDepartment of Ophthalmology, Ocular Surface Center, Baylor College of Medicine, Houston, TX, United StatesDepartment of Ophthalmology, Ocular Surface Center, Baylor College of Medicine, Houston, TX, United StatesDepartment of Ophthalmology, University of São Paulo, São Paulo, BrazilDepartment of Ophthalmology, Ocular Surface Center, Baylor College of Medicine, Houston, TX, United StatesDepartment of Ophthalmology, Ocular Surface Center, Baylor College of Medicine, Houston, TX, United StatesPurposeTo investigate IL-17 related mechanisms for developing dry eye disease in the Pinkie mouse strain with a loss of function RXRα mutation.MethodsMeasures of dry eye disease were assessed in the cornea and conjunctiva. Expression profiling was performed by single-cell RNA sequencing (scRNA-seq) to compare gene expression in conjunctival immune cells. Conjunctival immune cells were immunophenotyped by flow cytometry and confocal microscopy. The activity of RXRα ligand 9-cis retinoic acid (RA) was evaluated in cultured monocytes and γδ T cells.ResultsCompared to wild type (WT) C57BL/6, Pinkie has increased signs of dry eye disease, including decreased tear volume, corneal barrier disruption, corneal/conjunctival cornification and goblet cell loss, and corneal vascularization, opacification, and ulceration with aging. ScRNA-seq of conjunctival immune cells identified γδ T cells as the predominant IL-17 expressing population in both strains and there is a 4-fold increased percentage of γδ T cells in Pinkie. Compared to WT, IL-17a, and IL-17f significantly increased in Pinkie with conventional T cells and γδ T cells as the major producers. Flow cytometry revealed an increased number of IL-17+ γδ 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 γδ T and stimulatory activity of monocyte supernatant on γδ T cell IL-17 production. Compared to WT bone marrow chimeras, Pinkie chimeras have increased IL-17+ γδ 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.ConclusionThese findings indicate that RXRα suppresses generation of dry eye disease-inducing IL-17 producing lymphocytes s in the conjunctiva and identifies RXRα as a potential therapeutic target in dry eye.https://www.frontiersin.org/articles/10.3389/fmed.2022.849990/fullgamma delta (gammadelta) T cellsconjunctivadry eyeIL-17retinoic acidRXR alpha |
| spellingShingle | Jehan Alam Ghasem Yazdanpanah Rinki Ratnapriya Nicholas Borcherding Cintia S. de Paiva DeQuan Li Rodrigo Guimaraes de Souza Rodrigo Guimaraes de Souza Zhiyuan Yu Stephen C. Pflugfelder IL-17 Producing Lymphocytes Cause Dry Eye and Corneal Disease With Aging in RXRα Mutant Mouse Frontiers in Medicine gamma delta (gammadelta) T cells conjunctiva dry eye IL-17 retinoic acid RXR alpha |
| title | IL-17 Producing Lymphocytes Cause Dry Eye and Corneal Disease With Aging in RXRα Mutant Mouse |
| title_full | IL-17 Producing Lymphocytes Cause Dry Eye and Corneal Disease With Aging in RXRα Mutant Mouse |
| title_fullStr | IL-17 Producing Lymphocytes Cause Dry Eye and Corneal Disease With Aging in RXRα Mutant Mouse |
| title_full_unstemmed | IL-17 Producing Lymphocytes Cause Dry Eye and Corneal Disease With Aging in RXRα Mutant Mouse |
| title_short | IL-17 Producing Lymphocytes Cause Dry Eye and Corneal Disease With Aging in RXRα Mutant Mouse |
| title_sort | il 17 producing lymphocytes cause dry eye and corneal disease with aging in rxrα mutant mouse |
| topic | gamma delta (gammadelta) T cells conjunctiva dry eye IL-17 retinoic acid RXR alpha |
| url | https://www.frontiersin.org/articles/10.3389/fmed.2022.849990/full |
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