Dry Eye-Induced CCR7(+)CD11b(+) Cell Lymph Node Homing Is Induced by COX-2 Activities

作者：Ji Yong Woo; Seo Yuri; Choi Wungrak; Yeo Areum; Noh Hyemi; Kim Eung Kweon; Lee Hyung Keun^*

来源：Investigative Ophthalmology & Visual Science, 2014, 55(10): 6829-6838.

DOI：10.1167/iovs.14-14744

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

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 E-2/eicosanoid-prostanoid (PGE(2)/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-gamma(+), 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-II(high)CD11b(+) 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-gamma, TNF-alpha, 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/PGE(2)/EP axis contributes to immuno-inflammatory pathogenesis on the ocular surface and may be a novel therapeutic target in DE.

• 出版日期2014-10