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William Foulsham, xuhua tan, Yihe Chen, Afsaneh Amouzegar, Yizhi liu, Sunil Chauhan, Reza Dana; Corneal Epithelium-derived Thrombospondin-1 Regulates Dendritic Cell Maturation in Dry Eye Disease. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2065.
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© ARVO (1962-2015); The Authors (2016-present)
Thrombospondin (TSP)-1 is an important immunoregulatory factor produced by corneal epithelial cells (CECs). The purpose of this study was to investigate TSP-1-mediated regulation of dendritic cell maturation and the therapeutic efficacy of topical TSP-1 in dry eye disease (DED).
DED was induced in female C57BL/6 mice using a controlled environmental chamber for 14 days. mRNA and protein expression of TSP-1 in CECs was quantified by real-time PCR and flow cytometry at day 14. Activated bone marrow-derived dendritic cells (DCs) were co-cultured with CECs from either naïve or DED mice, and the frequencies of MHC-IIhi and CD86+ DCs were evaluated with flow cytometry. These experiments were repeated in the presence of recombinant TSP-1, and also anti-TSP-1 antibody. Finally, DED mice were treated topically with either recombinant TSP-1 or serum albumin. Infiltration and maturation of corneal dendritic cells, expression of inflammatory cytokines, and DED severity were investigated.
mRNA expression of TSP-1 was upregulated in CECs from DED mice compared to naïve mice (p<0.001). Although there was no significant difference in the frequencies of TSP-1-expressing CECs between naïve and DED mice, the mean fluorescence intensity of TSP-1 in CECs from DED mice was significantly increased (p=0.016). The frequencies of MHC-IIhi and CD86+ DCs in the presence of DED corneal epithelium were lower than in the presence of naïve corneal epithelium, although the value for CD86+ DCs failed to reach statistical significance (p=0.015 and p=0.117, respectively). Addition of recombinant TSP-1 to the co-culture system resulted in a significant decrease in frequencies of MHC-IIhi and CD86+ DCs (p=0.013 and p=0.008, respectively), while addition of TSP-1 antibody abrogated this suppressive effect (p=0.030 and p=0.015, respectively). Topical administration of recombinant TSP-1 was found to significantly inhibit the maturation and infiltration of corneal DCs, suppress inflammatory cytokine expression at the ocular surface, and reduce the corneal fluorescein staining score in DED mice (p<0.05).
Our results demonstrate that CEC-derived TSP-1 inhibits DC maturation, and that topical administration of recombinant TSP-1 suppresses ocular inflammation and reduces disease severity in DED mice.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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