June 2013
Volume 54, Issue 15
ARVO Annual Meeting Abstract  |   June 2013
MMP12 Regulation of Corneal Inflammation
Author Affiliations & Notes
  • Matilda Chan
    Ophthalmology/Proctor Foundation, Univ of California-San Francisco, San Francisco, CA
  • Jeffrey Lin
    Ophthalmology/Proctor Foundation, Univ of California-San Francisco, San Francisco, CA
  • Neeraj Ramakrishnan
    Ophthalmology/Proctor Foundation, Univ of California-San Francisco, San Francisco, CA
  • Zena Werb
    Anatomy, University of California, San Francisco, San Francisco, CA
  • Footnotes
    Commercial Relationships Matilda Chan, None; Jeffrey Lin, None; Neeraj Ramakrishnan, None; Zena Werb, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 1292. doi:
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      Matilda Chan, Jeffrey Lin, Neeraj Ramakrishnan, Zena Werb; MMP12 Regulation of Corneal Inflammation. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1292.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: An excessive accumulation of immune cells or a delay in the clearance of immune cells can result in corneal fibrosis and loss of corneal clarity. The underlying mechanisms that determine the kinetics of immune cell recruitment and clearance following corneal injury are not fully understood. Recent data has demonstrated that matrix metalloproteinases (MMPs) may have important regulatory roles in inflammation. We tested the hypothesis that MMP12 significantly contributes to the recruitment of inflammatory cells following corneal injury.

Methods: Alkaline burn injuries created by topical application of 0.1N NaOH were performed on corneas of WT and MMP12-/- mice. Corneas of Mmp12-/- and WT mice were collected 6 days after injury. Macrophage recruitment was assessed by whole mount technique. CCL2 expression levels were analyzed using qPCR, a protein array, and ELISA assay. The effect of blocking CCL2 on macrophage recruitment was evaluated by whole mount assay. The expression levels of macrophage M1 and M2 markers were measured using qPCR analysis.

Results: After injury, macrophage accumulation was significantly increased in MMP12-/- mice compared with WT mice. Analysis of the expression levels of several CCL chemokines demonstrated significantly elevated RNA and protein levels of CCL2 in Mmp12-/- corneas compared with WT corneas. The trafficking of macrophages into the central cornea following injury was significantly reduced by subconjunctival injections of CCL2 blocking antibodies. The expression of a macrophage M1 marker (TNF-α) was increased in injured corneas of Mmp12-/- mice while expression of a macrophage M2 marker (CD23) was reduced.

Conclusions: Excessive accumulation of macrophages following corneal injury and an M1 macrophage phenotype favor a fibrotic response to corneal injury. MMP12 appears to protect against a fibrotic response to injury by negatively regulating CCL2 expression, decreasing macrophage accumulation, and by promoting a tissue reparative M2 macrophage phenotype.

Keywords: 765 wound healing • 557 inflammation • 480 cornea: basic science  

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