Facilitation of neutrophil migration through the corneal stroma during keratitis: MMP-8 and chemokines.

摘要

Corneal opacification caused by extracellular damage and remodeling is a symptom of bacterial keratitis in which neutrophils are a critical part of its pathogenesis. While neutrophils are essential in the control and clearance of bacterial growth from the cornea, they can also be a predominant contributor to cornea stromal matrix damage due to their proteolytic and cytotoxic content. Targeting matrix metalloproteinases (MMPs) in disease has been enticing for drug development in modulating tissue damage given their variety of substrates. However, this task has proven arduous in part due to the non-specificity and difficult deliverability of the inhibitor, but also to the less understood biological roles MMPs have.; The migration of neutrophils to the site of inflammation is an essential component of the host inflammatory response, which relies on the coordinated action of chemoattraction, adhesion, and activation for controlled directional movement. Given that functions of MMPs can include modification of extracellular matrix and chemokine activity, we investigated their role in mediating neutrophil migration. Using a mouse model of lipopolysaccharide (LPS)-keratitis, we demonstrated that while MMP-8 and 9 MMP-9 are both expressed during inflammation, only MMP-8 participated in neutrophil migration through the central cornea. Furthermore, we found that this neutrophil migration was dependent on collagen degradation rather than processing LIX, a chemokine in which in addition to another chemokine, KC, we demonstrate is involved in recruiting neutrophils from the peripheral vessels into the corneal stroma. We also demonstrated that MMP-8 activity could result in generation of the chemotactic proline-glycine-proline (PGP) peptide, which also is involved in neutrophil migration through the corneal stroma. Based on these studies, we hypothesize that a normal role for MMP-8 in innate immunity is to aid in neutrophil migration through the cornea by exposing chemotactic neopeptides from the extracellular matrix.