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Denise Stephens, Feeling Yu Ting Chen, Nancy A McNamara; Corneal epithelial changes in Aire-/- mice mediated via the Jak/STAT signaling pathway. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):305.
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© ARVO (1962-2015); The Authors (2016-present)
A debilitating side effect of advanced dry eye disease is the loss of corneal epithelial integrity. The Aire-/- mouse model of immune-mediated aqueous deficient dry eye disease and Sjögren's syndrome develops corneal epitheliopathies, hyperproliferation, and squamous metaplasia. We hypothesized that the loss of corneal epithelial homeostasis in Aire-/- mice is a result of altered signaling whereby progenitor cells enter a transit amplifying cell state but fail to differentiate.
The differentiation state of Aire-/- corneal epithelial stem, basal, and differentiated cells was assessed by immunofluoresence. Whole genome expression analysis of Aire-/- corneas was utilized to identify candidate regulators of the Aire-/- corneal epithelial phenotype. Gene Ontology and Ingenuity Pathway Analysis were used to identify enriched gene categories and associated pathways. Activation of candidate regulators including STAT1 was assessed with immunoblotting and qPCR for known target genes. Aire-/- mice were treated with small molecule inhibitors to determine whether blocking STAT signaling in the corneal epithelium could rescue phenotype.
Corneal epithelial cell identity of Aire-/- mice is altered with increased epithelial proliferation, increased expression of basal epithelial markers, expansion of the stem cell compartment into the peripheral cornea, and decreased epithelial differentiation. Aire-/- mice have significantly altered expression of immune, proliferation, apoptosis, and cell cycle related genes. We linked the genes altered in Aire-/- mouse corneas to potential regulatory pathways such as Jak/STAT, which is activated via immune signaling to exert effects on cell proliferation, differentiation, and survival.<br /> We found increased STAT1 activation in Aire-/- mice and altered expression of STAT target genes. Treatment with STAT inhibitor fludarabine in Aire-/- mice decreased STAT activation.
Our results demonstrate that progenitor cell function is altered in Aire-/- mice. Our gene expression analysis identified a potential role for the Jak/STAT pathway in corneal epithelial cell identity, including STAT1, which is activated in Aire-/- mice. Our in vivo studies suggest that targeted small molecule therapies such as STAT inhibition may be an effective treatment in dry eye disease. Further studies will examine the molecular changes effected by STAT inhibition.
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