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The immunoregulatory role of corneal epithelium-derived thrombospondin-1 in dry eye disease.

ABSTRACT: PURPOSE:In this study, we examine the expression of corneal epithelium-derived thrombospondin-1 (TSP-1) and its immunomodulatory functions in a validated murine model of dry eye disease (DED). METHODS:DED was induced in female C57BL/6 using a controlled environment chamber (CEC) for 14 days. mRNA and protein expression of TSP-1 by corneal epithelial cells was quantified using real-time PCR and flow cytometry. Corneal epithelial cells from either naïve or DED mice were cultured with bone marrow derived dendritic cells (BMDCs) in the presence of IFN? for 48?h, and BMDC expression of MHC-II and CD86 was determined using flow cytometry. Next, either recombinant TSP-1 or anti-TSP-1 antibody was added to the co-culture, and BMDC expression of above activation markers was evaluated. Finally, either DED mice were topically treated with either recombinant TSP-1 or human serum albumin (HSA), and maturation of corneal DCs, expression of inflammatory cytokines, and DED severity were investigated. RESULTS:mRNA expression of TSP-1 by the corneal epithelium was upregulated in DED. Corneal epithelial cells derived from mice with DED demonstrated an enhanced capacity in suppressing BMDC expression of MHC-II and CD86 relative to wild type mice, and this effect was abrogated by TSP-1 blockade and potentiated by recombinant TSP-1. Finally, topical application of recombinant TSP-1 significantly suppressed corneal DC maturation and mRNA expression of pro-inflammatory cytokines, and ameliorated disease severity in mice with DED. CONCLUSIONS:Our study elucidates the function of epithelium-derived TSP-1 in inhibiting DC maturation and shows its translational potential to limit corneal epitheliopathy in DED.

SUBMITTER: Tan X

PROVIDER: S-EPMC6289260 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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The immunoregulatory role of corneal epithelium-derived thrombospondin-1 in dry eye disease.

Tan Xuhua X Chen Yihe Y Foulsham William W Amouzegar Afsaneh A Inomata Takenori T Liu Yizhi Y Chauhan Sunil K SK Dana Reza R

The ocular surface 20180725 4

<h4>Purpose</h4>In this study, we examine the expression of corneal epithelium-derived thrombospondin-1 (TSP-1) and its immunomodulatory functions in a validated murine model of dry eye disease (DED).<h4>Methods</h4>DED was induced in female C57BL/6 using a controlled environment chamber (CEC) for 14 days. mRNA and protein expression of TSP-1 by corneal epithelial cells was quantified using real-time PCR and flow cytometry. Corneal epithelial cells from either naïve or DED mice were cultured wit ...[more]

PMID: 30055331

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Project description:PurposeTo evaluate the association between symptoms and signs of dry eye diseases (DED) with corneal biomechanical parameters.MethodsThis cross-sectional study enrolled 81 participants without history of ocular hypertension, glaucoma, keratoconus, corneal edema, contact lens use, diabetes, and ocular surgery. All participants were evaluated for symptoms and signs of DED using OSDI questionnaire, tear film break-up time (TBUT), conjunctival and corneal staining (NEI grading) and Schirmer test. Corneal biomechanical parameters were obtained using Corvis ST. Mixed-effects linear regression analysis was used to determine the association between symptoms and signs of DED with corneal biomechanical parameters. Difference in corneal biomechanical parameter between participants with low (Schirmer value ≤10 mm; LT group) and normal (Schirmer value >10mm; NT group) tear production was analyzed using ANCOVA test.ResultsThe median OSDI scores, TBUT, conjunctival and corneal staining scores as well as Schirmer test were 13±16.5 (range; 0-77), 5.3±4.2 seconds (range; 1.3-11), 0±1 (range; 0-4), 0±2 (ranges; 0-9) and 16±14 mm (range; 0-45) respectively. Regression analysis adjusted with participants' refraction, intraocular pressure, and central corneal thickness showed that OSDI had a negative association with highest concavity radius (P = 0.02). The association between DED signs and corneal biomechanical parameters were found between conjunctival staining scores with second applanation velocity (A2V, P = 0.04), corneal staining scores with second applanation length (A2L, P = 0.01), Schirmer test with first applanation time (A1T, P = 0.04) and first applanation velocity (P = 0.01). In subgroup analysis, there was no difference in corneal biomechanical parameters between participants with low and normal tear production (P>0.05). The associations were found between OSDI with time to highest concavity (P<0.01) and highest displacement of corneal apex (HC-DA, P = 0.04), conjunctival staining scores with A2L (P = 0.01) and A2V (P<0.01) in LT group, and Schirmer test with A1T (P = 0.02) and HC-DA (P = 0.03), corneal staining scores with A2L (P<0.01) in NT group.ConclusionsAccording to in vivo observation with Corvis ST, patients with DED showed more compliant corneas. The increase in dry eye severity was associated with the worsening of corneal biomechanics in both patients with low and normal tear production.

Project description:Autoimmune-mediated dry eye disease is a pathological feature of multiple disorders including Sjögren's syndrome, lupus and rheumatoid arthritis that has a life-long, detrimental impact on vision and overall quality of life. Although late stage disease outcomes such as epithelial barrier dysfunction, reduced corneal innervation and chronic inflammation have been well characterized in both human patients and mouse models, there is little to no understanding of early pathological processes. Moreover, the mechanisms underlying the loss of cornea homeostasis and disease progression are unknown. Here, we utilize the autoimmune regulatory (Aire)-deficient mouse model of autoimmune-mediated dry eye disease in combination with genome wide transcriptomics, high-resolution imaging and atomic force microscopy to reveal a potential extracellular matrix (ECM)-biomechanical-based mechanism driving cellular and morphological changes at early disease onset. Early disease in the Aire-deficient mouse model is associated with a mild reduction in tear production and moderate immune cell infiltration, allowing for interrogation of cellular, molecular and biomechanical changes largely independent of chronic inflammation. Using these tools, we demonstrate for the first time that the emergence of autoimmune-mediated dry eye disease is associated with an alteration in the biomechanical properties of the cornea. We reveal a dramatic disruption of the synthesis and organization of the extracellular matrix as well as degradation of the epithelial basement membrane during early disease. Notably, we provide evidence that the nerve supply to the cornea is severely reduced at early disease stages and that this is independent of basement membrane destruction or significant immune cell infiltration. Furthermore, diseased corneas display spatial heterogeneity in mechanical, structural and compositional changes, with the limbal compartment often exhibiting the opposite response compared to the central cornea. Despite these differences, however, epithelial hyperplasia is apparent in both compartments, possibly driven by increased activation of IL-1R1 and YAP signaling pathways. Thus, we reveal novel perturbations in corneal biomechanics, matrix organization and cell behavior during the early phase of dry eye that may underlie disease development and progression, presenting new potential targets for therapeutic intervention.

Dataset Information

The immunoregulatory role of corneal epithelium-derived thrombospondin-1 in dry eye disease.

Publications

The immunoregulatory role of corneal epithelium-derived thrombospondin-1 in dry eye disease.

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