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Invest Ophthalmol Vis Sci. 2014 Sep 25;55(10):6829-38. doi: 10.1167/iovs.14-14744.

Dry eye-induced CCR7+CD11b+ cell lymph node homing is induced by COX-2 activities.

Author information

1
Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Korea.
2
Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Korea Institute of Corneal Dystrophy Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Korea.

Abstract

PURPOSE:

We aimed to determine the role of CCR7+CD11b+ cell lymph node (LN) homing and T-cell differentiation in dry eye (DE)-induced immunopathogenesis and investigate the therapeutic effects of cyclooxygenase-2 (COX-2) and prostaglandin E2/eicosanoid-prostanoid (PGE2/EP) inhibitors against DE.

METHODS:

Six-week-old female C57BL/6 mice were housed in a controlled-environment chamber and administered topical selective COX-2 inhibitors or EP2 antagonists. Expression of major histocompatibility complex (MHC)-IIhigh, CD11b+, CCR7+, IFN-γ+, IL-17+, and CD4+ in the corneas and draining LNs was evaluated using flow cytometry. Mixed lymphocyte reactions (MLRs) with carboxyfluorescein diacetate succinimidyl ester labeling and intracellular cytokine staining were used to verify DE-induced corneal dendritic cell function. mRNA expression of COX-2, EPs, and proinflammatory cytokines in ocular surface was evaluated using quantitative RT-PCR and immunohistochemical staining.

RESULTS:

Dry eye significantly increased MHC-IIhighCD11b+ and CCR7+CD11b+ cells in the cornea and LNs, and MLR revealed CCR7+CD11b+ cells from DE corneas stimulated IL-17+CD4+ cell proliferation. mRNA levels of COX-2, EP2, IFN-γ, TNF-α, IL-6, and IL-17 were significantly higher in DE ocular surface but were suppressed by topical COX-2 inhibitors and EP2-specific blockers. Immunohistochemical staining showed COX-2 and matrix metalloproteinase expression in DE corneal epithelia that was diminished by both topical treatments. Furthermore, both topical treatments significantly reduced frequencies of MHC-IIhigh, CD11b+, and CCR7+CD11b+ cells in the corneas and LNs, but also IL-17+CD4+ cells in LNs.

CONCLUSIONS:

Topical COX-2/EP2 treatment reduces CCR7+CD11b+ cells on the ocular surface with inhibition of cellular LN homing and suppresses Th17 immune response, suggesting the COX-2/PGE2/EP axis contributes to immuno-inflammatory pathogenesis on the ocular surface and may be a novel therapeutic target in DE.

KEYWORDS:

EP receptor; chemokine receptor CCR7; cyclooxygenase-2 (COX-2); dendritic cell; dry eye disease; prostaglandin E2

PMID:
25257053
DOI:
10.1167/iovs.14-14744
[Indexed for MEDLINE]

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