It is well understood that the enzymatic activity of MMPs largely contribute to modulating normal, as well as pathologic, conditions of the ECM.
16 During ocular wound healing, MMP expression and activation are important in basement membrane remodeling, wound contraction, debris clearance, and fibrotic repair tissue deposition.
1 Complementary to, yet independent of, proteolytic activity of these molecules, MMPs can influence molecular mediators of inflammation through the generation of both pro- and anti-inflammatory signals.
1 MMP-7 has been shown to have a protective response in the small intestine by proteolytic processing of the mature form of α-defensin,
17 an antimicrobial peptide expressed by Paneth cells. MMP-2, -3, -7, and -9 have been shown to release TGF-β from the ECM, allowing for its subsequent activation
18,19 and execution of immunomodulatory functions, which include selective stimulation of ECM components. This family of proteolytic enzymes has also been linked to both normal and pathologic neovascularization by regulating the bioavailability of angiogenic factors, such as vascular endothelial growth factor and epithelial growth factor.
1 A previous study from our laboratory showed that MMP-9 (gelatinase B) regulates corneal immune function by degrading collagen IV and upregulating chemotactic cytokines/chemokines IL-1β and macrophage inflammatory protein (MIP)-2.
20 Results from the present study demonstrate disparate expression profile for MMP-2 in the cornea of BALB/c versus B6 mice. This differential MMP expression is thought to influence matrix regeneration or degradation, thus potentiating resistance (BALB/c) or susceptibility (B6) after
P. aeruginosa-induced ocular infection. When further explored, it was found that MMP-2 (gelatinase A), noted for its role in wound repair and development,
1,2,21 is upregulated late in BALB/c mice; thus, corresponding to a shift in the immune response toward wound healing and tissue restoration. The MMP-2 data corresponded with a recent study of MMP expression during fungal keratitis.
22 The investigators spatially localized MMP-2 expression to corneal epithelium using immunofluorescent staining and immunohistochemistry. Given that the BALB/c cornea remains more intact than B6 after bacterial keratitis, we hypothesize that during the wound-healing phase, higher MMP-2 levels are due to (1) direct protein expression by corneal epithelial cells or (2) the indirect production of epithelial-derived signals that augment MMP-2 expression. MMP-2 levels are lower in B6 mice since the corneal epithelium is, in large part, decimated, which strengthens the supposition that MMP-2 expression in the cornea is dependent on corneal epithelial cells and warrants additional investigation. In addition, given that MMP-2 is linked to corneal healing, remodeling, and maintenance, we surmise that the decrease in protein levels for both BALB/c and B6 mice at 1 day pi is an effort to clear the
Pseudomonas infection, which is then followed by increased levels of MMP-2 focused on healing and reconstitution of the stroma.