Interferon-gamma deficiency protects against aging-related goblet cell loss.

Eugene A Volpe,Mahira Zaheer,Changjun Wang,Xiaobo Zhang,Flavia L Barbosa,Stephen C Pflugfelder,Cintia S De Paiva,Johanna Tukler Henriksson

doi:10.18632/oncotarget.11872

Eugene A Volpe, Mahira Zaheer + Show 6 more

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https://doi.org/10.18632/oncotarget.11872

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Abstract

Aging is a well-recognized risk factor for dry eye. Interferon-gamma (IFN-γ) has been implicated in conjunctival keratinization and goblet cell loss in dry eye. We investigated the role of IFN-γ in age-related dry eye by evaluating young (8 weeks) and aged (15 months; 15M) C57BL/6 (B6) and IFN-γKO mice. Age effects on the conjunctiva and cornea epithelium were assessed with PAS staining and corneal staining, respectively. Expression of T cell-related cytokines (IL-17A, IFN-γ), chemokines (CXCL10 and CCL20), in the ocular surface epithelium was evaluated by real time PCR. A significant decrease in filled goblet cells was noted in 15M B6 mice and this was significantly lower than age and sex-matched IFN-γKO mice. Aged male B6 had significantly higher IFN-γ, and CXCL10 mRNA in their conjunctiva than female B6 mice. Aged IFN-γKO females had significantly higher IL-17A mRNA in conjunctiva than IFN-γKO males and B6 mice. Corneal barrier dysfunction was observed in 15M female B6 and aged IFN-γKO mice of both sexes; however it was significantly higher in IFN-γKO compared to B6 mice. While there was a significant increase in IL 17A, and CCL20 in corneas of aged female B6 and IFN-γKO mice compared to males, these changes were more evident in aged female IFN-γKO group.Partial resistance of IFN-γKO mice to aging-induced goblet cell loss indicates IFN-γ is involved in the age-related decline in conjunctival goblet cells. Increased corneal IL-17A expression paralleled corneal barrier disruption in aging female of both strains. IFN-γ appears to suppress IL-17A on the ocular surface.

Highlights

Aging is a well-known-risk factor for dry eye
15M IFN-KO mice P < 0.05, Figure 1A-1B) compared to its baseline, this was significantly less than the age-related goblet cell loss observed in in B6 mice (~24% vs. 40%, respectively)
We evaluated expression of Th1 (IFN-γ, C-X-C motif chemokine ligand 10 (CXCL10)), Th17 (IL-17A, CC-chemokine attractant ligand 20 (CCL20)), and Th2 (IL-13) related factors in conjunctiva of young and old mice by real time PCR

Summary

Introduction

Aging is a well-known-risk factor for dry eye. Prevalence of dry eye disease increases with age after the 4th decade and it’s more prevalent in women [1,2,3]. A frequent finding in dry eye is keratinization of the ocular surface epithelium and loss of goblet cells [4,5,6,7,8]. Both IFN-γ and IL-17 have been implicated in the pathogenesis of dry eye associated ocular surface epithelial disease [912]. A compensatory auto proliferation of existing, mature T-cells may lead to the expansion of CD4 positive (+) T-cells These cells are resistant to apoptosis and have been shown to be associated with a variety of autoimmune disorders such as rheumatoid arthritis, multiple sclerosis, and diabetes mellitus [14]

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