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Qiong Liu, Zhijie Li, Wanyu Zhang, Alan Burns, C. Wayne Smith; The Contribution Of Natural Killers Cells To Corneal Wound Healing. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3141.
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To define the role of natural killer (NK) cells in corneal wound healing.
A 2 mm epithelial abrasion was performed in the corneas of TCRdelta-/-, ICAM-1-/-, CD11a-/-, CD11b-/- mice, and wild-type mice with NK cell, gamma delta T cell, and neutrophil depletion or adoptive transfer of isolated NK cells from the spleen. Corneas were collected at 6, 12, 18, 24, 30, 36 and 72 hrs after injury. The phenotypes and dynamics of NK cell trafficking to wounded corneas were examined and analyzed using fluorescence deconvolution microscopy. The level of inflammatory chemokines was measured through ELISA, protein array, and RT-PCR. In addition, the effect of NK cell blocking or depletion on re-epithelialization, nerve regeneration, and leukocyte recruitment was observed by whole mount techniques.
In the normal limbus, some CD3- NKp46+ CD94+ and CD94- NK cells were found in the epithelium and corneal stroma. After wounding, many NK cells migrated into the limbus and corneal stroma, peaking at 24 hrs. The immigrated cells were of the NKp46+ NK1.1+ EOMES+ CD3- IL-22- ROR gamma t- CD94- phenotype. In TCRdelta-/-, ICAM-1-/-, CD11a-/-, CD11b-/- mice, and gamma delta T cell depleted mice, the NK cell accumulation was significantly depressed. Neutrophil depleted animals, however, had normal NK cell accumulation. The trafficking of NK cells into the cornea was significantly reduced by topically treating mice with CXCL10, or MCP-1 blocking antibodies. Adoptively transferred NK cell migration into the wounded cornea was significantly reduced by ex vivo treatment with CXCR3 or CCR2 blocking antibodies, but not anti-NKG2D. Functional blocking of NKG2D or depletion of NK cells significantly increased accumulation of neutrophils in the wounded cornea, and corneal nerve regeneration and epithelial healing were significantly inhibited.
Though neutrophils are important for early wound healing, excess accumulation can cause tissue injury. NK cells may be actively involved in corneal wound healing by modulating the acute inflammatory reaction and limiting the accumulation of neutrophils.
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