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Denise Stephens, Feeling Chen, Sarah Knox, Nancy A McNamara; IFNγ mediates corneal neuropathy in Aire KO mice and alters epithelial progenitor cells. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5046.
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Dry eye disease (DED) is a common disorder with limited treatment options. One side effect observed in both patients and mouse models of immune-mediated DED is loss of corneal innervation. Yet the potential functional role of corneal denervation in dry eye pathogenesis is often overlooked. Ocular surface innervation plays a role in maintaining tear secretion, epithelial integrity and normal stem cell behavior. In the autoimmune regulator knock out (Aire KO) mouse model of immune-mediated, aqueous-deficient dry eye, we observed loss of corneal innervation, breakdown of epithelial integrity and altered corneal epithelial stem/progenitor cell (EPC) activation and differentiation. Recent research has shown that peripheral neuropathy in Aire KO mice is mediated through IFNγ-secreting CD4+ Th1 cells. We hypothesized that corneal denervation in Aire KO mice was mediated through IFNγ and lead to altered surface integrity and EPC activity.
Inflammation and innervation of Aire KO mouse corneas were examined by immunostaining with markers of neurons (β3-tubulin), epithelia (E-cadherin) and inflammation (CD4). To characterize the role of IFNγ in corneal neuropathy, we developed an ex vivo culture model of Aire KO or IFNγ-treated corneas. Expression changes of neuromodulators and corneal EPC markers were evaluated with QPCR.
Adult Aire KO mice have reduced corneal innervation compared to littermate controls. β3-tubulin staining was decreased in postnatal day (P)7 and P14, but not P1 Aire KO mice. Similarly, CD4 staining was present in P7 and P14 Aire KO mice, but not P1. Expression of neurotrophic factors Ntf3, Bdnf, and Gdnf and BDNF receptor Ntrk2 were downregulated in Aire KO corneas. Ntf3, Bdnf, and Ntrk2 were also downregulated in ex vivo corneas treated with IFNγ for 24h. Downregulation of neuronal guidance factor, Sema3a, in both Aire KO and IFNγ-treated corneas suggested a defect in axonal pathfinding, while a corresponding increase in basal progenitor cell marker, Krt14, suggested altered EPC behavior.
Corneas of Aire KO mice are denervated and the development of denervation coincides with inflammation. Our data suggest that altered expression of neuromodulators and axonal guidance factors contribute to loss of innervation, with an associated defect in EPC function. In future studies we will examine the interplay between the immune and nervous systems in the development of DED.
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