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Y.-T. Chen, K. Nikulina, M. Gallup, N. McNamara, N. McNamara; Squamous Metaplasia of the Ocular Surface Epithelium in Autoimmune Regulator-deficient Mice is IL-1R Dependent. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2641.
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© ARVO (1962-2015); The Authors (2016-present)
Sjögren syndrome (SS) causes an autoimmune-mediated aqueous-deficient keratoconjunctivitis sicca (KCS) that leads to squamous metaplasia of the ocular mucosal surface and a decrease in mucin-secreting goblet cells. Although the proinflammatory cytokine IL-1 has been implicated in the pathogenesis of SS-KCS, its contribution to pathological keratinization remains unclear. The authors hypothesize that IL-1 signaling is critical for the development of pathological keratinization in autoimmune-mediated KCS. To test this hypothesis, we used gene-targeted knock out mice deficient in both the autoimmune regulator gene (Aire) and the IL-1R to manifest a SS-like KCS in the absence of IL-1 signaling.
Aire-/- single knock out (SKO) and Aire-/- IL-1R-/- double knockout (DKO) mice were used to evaluate the role of IL-1 in SS-KCS. Epithelial integrity was scored by lissamine green staining. Keratinization was quantified using both the squamous differentiation biomarker, small proline-rich protein 1B (SPRR1B) and the goblet cell-specific mucin, MUC5AC. Immunostaining of CD4+ and CD8+ lymphocytes was used to exam the severity of T cell infiltration in the presence and absence of IL-1R.
Compared to wild type (WT) mice, lissamine green staining was increased 7.93+2.60 and 4.17+2.68 fold in SKO and DKO mice, repectively (p <0.05). Intensity of SPRR1B immunostaining revealed a 2.0+0.25 and 1.09+0.01 fold increase in SKO and DKO mice, respectively, compared to WT (p <0.05). MUC5AC+ goblet cells in the tarsal conjunctiva were reduced in SKO mice, whereas no difference was noted between DKO and WT mice. Inflammatory profiling of SKOs demonstrated predominantly CD4+ T cell infiltrates in the subepithelial stroma of the limbus and conjunctiva that were reduced 42%, on average, in DKOs. Alternatively, there was no difference in CD8+ cells between SKOs and DKOs. Both T cell types were negligible in WTs.
Aire-/- mice have compromised epithelial integrity, squamous metaplasia and T cell infiltration in the ocular surface epithelium. Squamous metaplasia and inflammation are significantly reduced in Aire-/-IL1R-/- mice suggesting an important role for IL-1 signaling in autoimmune-induced ocular keratinization.
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