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Ying-Ting Chen, Stanislav Lazarev, Ahmad F. Bahrami, Lisa B. Noble, Delu Zhou, Marianne Gallup, Nancy A. McNamara; Interleukin-1 Signaling Downregulates Ocular Surface Phenotype Regulator, Pax6, In Keratinizing Squamous Metaplasia Associated With Sjögren’s Syndrome. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2094.
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Squamous metaplasia (SQM) is a blinding, end-stage ocular manifestation of severe Sjögren’s Syndrome (SS). We recently identified interleukin-1 (IL-1) as a key effector cytokine in the immunopathogenesis of SS-associated SQM. We hypothesized that Pax6, a master transcriptional regulator of corneal phenotype, is downregulated in SS dry eye-associated SQM in response to pathological activation of IL-1 signaling.
Pax6 expression in ocular epithelia was studied in SS patients and in a murine model of SQM, autoimmune regulator (Aire)-deficient mice. The effect of IL-1 signaling on Pax6 expression was explored by qPCR and immunoflourescence in non-disease susceptible SCID mice after adoptive transfer (AT) of CD4+-enriched T cells using the following
On average, mRNA of Pax6 was reduced 42% and 51% in SS patients and Aire KO mice, respectively. Regression analysis revealed a negative correlation between Pax6 and IL-1β in the ocular epithelia of Aire KO mice at the transcriptional level (R2=0.46, p<0.01). AT of CD4+ T cells from Aire KO and Aire/IL-1R1 DKO mice to SCID recipients with functional IL-1R1 caused a 61% and 89% reduction in Pax6 mRNA, respectively (p< 0.05 in both AT groups). In contrast, Pax6 expression in IL-R1-deficient SCID mice receiving CD4+ T cells derived from Aire KO mice was not significantly different from that of wildtype (WT) control mice. Immunofluorescence of Pax6 revealed a nuclear expression pattern throughout the entire ocular epithelia in WT control mice and SCID recipients of AT, deficient in IL-1R1. In contrast, Pax6 immunoreactivity was essentially negative in IL-1R1-sufficient SCID mice receiving CD4+ cells from Aire KO or Aire/IL-1R1 DKO mice.
Pax6 is downregulated in human SS patients and in the Aire KO mouse model of SS. Using an AT approach, we determined a crucial role for IL-1 signaling in the resident cells of ocular surface tissues for the downregulation of Pax6 in autoimmune-mediated SQM.
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