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

 Yong Woo Ji  ;  Yuri Seo  ;  Wungrak Choi  ;  Areum Yeo  ;  Hyemi Noh  ;  Eung Kweon Kim  ;  Hyung Keun Lee 
 Investigative Ophthalmology & Visual Science, Vol.55(10) : 6829-6838, 2014 
Journal Title
 Investigative Ophthalmology & Visual Science 
Issue Date
Animals ; CD11b Antigen/immunology* ; Cell Proliferation ; Cornea/metabolism* ; Cornea/pathology ; Cyclooxygenase 2/genetics* ; Cyclooxygenase 2/metabolism ; Disease Models, Animal ; Dry Eye Syndromes/genetics ; Dry Eye Syndromes/immunology* ; Dry Eye Syndromes/metabolism ; Female ; Flow Cytometry ; Gene Expression Regulation* ; Immunohistochemistry ; Lymph Nodes/immunology ; Lymph Nodes/metabolism ; Mice ; Mice, Inbred C57BL ; RNA, Messenger/genetics* ; Real-Time Polymerase Chain Reaction ; Receptors, CCR7/immunology* ; Receptors, CCR7/metabolism ; Receptors, Lymphocyte Homing/immunology ; Receptors, Lymphocyte Homing/metabolism
EP receptor ; chemokine receptor CCR7 ; cyclooxygenase-2 (COX-2) ; dendritic cell ; dry eye disease ; prostaglandin E2
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.
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1. College of Medicine (의과대학) > Dept. of Ophthalmology (안과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
Yonsei Authors
Kim, Eung Kweon(김응권) ORCID logo https://orcid.org/0000-0002-1453-8042
Noh, Hae Mi(노혜미)
Yeo, Areum(여아름)
Lee, Hyung Keun(이형근) ORCID logo https://orcid.org/0000-0002-1123-2136
Choi, Wungrak(최웅락) ORCID logo https://orcid.org/0000-0002-3015-2502
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