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Immunology - Molecular Biology - Ophthalmology - Physiology


Disruption of TGF-ß Signaling Improves Ocular Surface Epithelial Disease in Experimental Autoimmune Keratoconjunctivitis Sicca
Published: Wednesday, December 14, 2011
Author: Cintia S. De Paiva et al.

by Cintia S. De Paiva, Eugene A. Volpe, Niral B. Gandhi, Xiaobo Zhang, Xiaofen Zheng, John D. Pitcher, William J. Farley, Michael E. Stern, Jerry Y. Niederkorn, De-Quan Li, Richard A. Flavell, Stephen C. Pflugfelder

Background

TGF-ß is a pleiotropic cytokine that can have pro- or anti-inflammatory effects depending on the context. Elevated levels of bioactive TGF-ß1 in tears and elevated TGF-ß1mRNA transcripts in conjunctiva and minor salivary glands of human Sjögren's Syndrome patients has also been reported. The purpose of this study was to evaluate the response to desiccating stress (DS), an experimental model of dry eye, in dominant-negative TGF-ß type II receptor (CD4-DNTGFßRII) mice. These mice have a truncated TGF-ß receptor in CD4+ T cells, rendering them unresponsive to TGF-ß.

Methodology/Principal Findings

DS was induced by subcutaneous injection of scopolamine and exposure to a drafty low humidity environment in CD4-DNTGFßRII and wild-type (WT) mice, aged 14 weeks, for 5 days. Nonstressed (NS) mice served as controls. Parameters of ocular surface disease included corneal smoothness, corneal barrier function and conjunctival goblet cell density. NS CD4-DNTGFßRII at 14 weeks of age mice exhibited a spontaneous dry eye phenotype; however, DS improved their corneal barrier function and corneal surface irregularity, increased their number of PAS+ GC, and lowered CD4+ T cell infiltration in conjunctiva. In contrast to WT, CD4-DNTGFßRII mice did not generate a Th-17 and Th-1 response, and they failed to upregulate MMP-9, IL-23, IL-17A, ROR?T, IFN-? and T-bet mRNA transcripts in conjunctiva. RAG1KO recipients of adoptively transferred CD4+T cells isolated from DS5 CD4-DNTGFßRII showed milder dry eye phenotype and less conjunctival inflammation than recipients of WT control.

Conclusions/Significance

Our results showed that disruption of TGF-ß signaling in CD4+ T cells causes paradoxical improvement of dry eye disease in mice subjected to desiccating stress.

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