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Matilda F Chan, Marie Wolf, Emily Khuc; MMP12 Regulates CCL2 Expression in Mouse and Human Corneas. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):737.
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© ARVO (1962-2015); The Authors (2016-present)
Macrophages are important in the fibrotic response to corneal injury. MMP12 (macrophage metalloelastase) is a secreted protease that degrades extracellular matrix during tissue inflammation. We previously showed that corneas of MMP12-/- mice have increased macrophage infiltration and elevated CCL2 chemokine levels following injury compared with wild-type (WT) mice. In this study we tested the hypothesis that MMP12 negatively regulates CCL2 and CCR2 expression in mouse and human corneal tissue.
Alkaline burn injuries created by topical application of 0.1N NaOH were performed on corneas of littermate WT and MMP12-/- mice. Corneas of Mmp12-/- and WT mice were collected prior to injury, and 1, 4, and 6 days after injury and processed for RNA. CCL2 and CCR2 expression levels were analyzed using qPCR assay. Total RNA was also extracted from 8 full-thickness corneal samples from patients undergoing penetrating keratoplasty for corneal scarring due to various corneal diseases and from 3 normal corneal samples obtained from an eye bank. MMP12, CCL2, and CCR2 expression levels were analyzed using qPCR assay.
The mouse injury model demonstrated early upregulation of CCL2 and CCR2 expression after injury with significantly elevated expression levels at 1 day post-injury. At 4 and 6 days post-injury, CCL2 and CCR2 expression levels were at or closer to pre-injury levels. For all time points tested, CCL2 and CCR2 expression levels were higher in MMP12-/- mice compared with WT mice. Analysis of human corneas showed that 3 out of 8 diseased corneal samples expressed MMP12. In these 3 samples, CCL2 expression levels were inversely correlated with MMP12 expression levels while CCR2 expression levels showed no correlation.
Excessive accumulation of macrophages following corneal injury favors a fibrotic response to corneal injury. The CCL2 chemokine mediates macrophage recruitment into injured corneas and our results support our hypothesis that MMP12 negatively regulates CCL2 expression in both injured mouse and diseased human corneal tissue.<br />
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