MMP generated matrikines

Abstract

Matrikines originate from the fragmentation of extracellular matrix proteins and regulate cellular activities by interacting with specific receptors. Matrikines are implicated in inflammation, immune responses, organ development, wound repair, angiogenesis, atherosclerosis, tumor progression and metastasis due to their ability to alter cellular migration, chemotaxis, and mitogenesis. Matrix metalloproteinases (MMPs) degrade extracellular matrix components under normal circumstances and in disease processes. Of the 20 MMPs identified, MMP-1, MMP-2, MMP-8, MMP-9, and MMP-12 have been implicated in regulating the matrikines Val-Gly-Val-Ala-Pro-Gly (elastin peptide) and proline-glycine-proline (PGP). Elastin peptide fragments are generated by elastolytic enzymes and have implications in atherosclerosis, neovascularization, chronic obstructive pulmonary disease, skin disease, as well as tumor invasion and spread. PGP is produced through a multistep pathway that liberates the tripeptide fragment from extracellular collagen. PGP is best described for its role in neutrophil chemotaxis and is implicated in the pathogenesis of corneal ulcers and in chronic lung conditions. In chronic cigarette smoke related lung disease, the PGP pathway can become a self-propagating cycle of inflammation through cigarette-smoke mediated inhibition of leukotriene A4 hydrolase, the enzyme responsible for degrading PGP and halting acute inflammation. This review highlights the roles of MMPs in generating these important matrikines.

Keywords: COPD; Elastin; Matrix metalloproteinase; Proline–glycine–proline.

Copyright © 2015. Published by Elsevier B.V.

Figures

Figure 1. Central role of MMP-derived PGP in smoking-induced pulmonary inflammation

(1) In response to infection or injury, resident cells within the lung release chemoattractants that promote neutrophil recruitment from the vasculature into the tissue. Epithelial cells and alveolar macrophages, for example, release IL-8 that binds to CXCR1/2 on the neutrophil surface and promote recruitment. The intracellular activity of LTA4H within leukocytes can generate the lipid mediator LTB4 that promotes neutrophil recruitment by binding to LTB4 receptor (BLT1). (2) Neutrophils release an array of proteases within the lung tissue—the coordinated action of matrix metalloproteinases (MMPs; especially MMP-1, -8, and -9) and prolyl endopeptidase (PE) released from the neutrophil targets extracellular matrix collagen, releasing the neutrophil chemoattractant, proline-glycine-proline (PGP). PGP binds CXCR1/2 on the neutrophil and sustains neutrophil recruitment. (3) To terminate PGP-directed neutrophilic inflammation, LTA4H is released into an extracellular environment to degrade the peptide. (4) Acrolein, derived from cigarette smoke or physiologically during inflammation (lipid peroxidation, metabolism of threonine or spermine), can inhibit LTA4H-mediated degradation of PGP, allowing the peptide to accumulate and maintain neutrophilic inflammation. (5) Acrolein (and other components of cigarette smoke) can also chemically acetylate PGP on its N terminus, completely protecting the peptide from LTA4H-mediated degradation, and thus facilitating neutrophil recruitment. AcPGP = acetylated PGP; PE = prolyl endopeptidase. Reproduced with permission.

Figure 2. A model of persistent matrikine production and neutrophilic inflammation

During chronic PMN inflammation, collagen is hydrolyzed and releases AcPGP causing ongoing neutrophilic influx (A). In addition to causing neutrophilic influx, AcPGP ligation of CXCR1 and CXCR2 leads to intracellular ERK phosphorylation and activation (B) and degranulation of MMP-9 from tertiary granules of neutrophils (C and D). This MMP-9 acts on exposed collagen leading to AcPGP generation (E) and a feed-forward inflammatory response on neutrophils (F). Reproduced with permission .