A self-propagating matrix metalloprotease-9 (MMP-9) dependent cycle of chronic neutrophilic inflammation

PLoS One. 2011 Jan 13;6(1):e15781. doi: 10.1371/journal.pone.0015781.


Background: Chronic neutrophilic inflammation is a poorly understood feature in a variety of diseases with notable worldwide morbidity and mortality. We have recently characterized N-acetyl Pro-Gly-Pro (Ac-PGP) as an important neutrophil (PMN) chemoattractant in chronic inflammation generated from the breakdown of collagen by the actions of MMP-9. MMP-9 is present in the granules of PMNs and is differentially released during inflammation but whether Ac-PGP contributes to this ongoing proteolytic activity in chronic neutrophilic inflammation is currently unknown.

Methodology/principal findings: Utilizing isolated primary blood PMNs from human donors, we found that Ac-PGP induces significant release of MMP-9 and concurrently activates the ERK1/2 MAPK pathway. This MMP-9 release is attenuated by an inhibitor of ERK1/2 MAPK and upstream blockade of CXCR1 and CXCR2 receptors with repertaxin leads to decreased MMP-9 release and ERK 1/2 MAPK activation. Supernatants obtained from PMNs stimulated by Ac-PGP generate more Ac-PGP when incubated with intact collagen ex vivo; this effect is inhibited by an ERK1/2 pathway inhibitor. Finally, clinical samples from individuals with CF demonstrate a notable correlation between Ac-PGP (as measured by liquid chromatography-tandem mass spectrometry) and MMP-9 levels even when accounting for total PMN burden.

Conclusions/significance: These data indicate that ECM-derived Ac-PGP could result in a feed-forward cycle by releasing MMP-9 from activated PMNs through the ligation of CXCR1 and CXCR2 and subsequent activation of the ERK1/2 MAPK, highlighting for the first time a matrix-derived chemokine (matrikine) augmenting its generation through a discrete receptor/intracellular signaling pathway. These findings have notable implications to the development unrelenting chronic PMN inflammation in human disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chemotactic Factors / physiology*
  • Chronic Disease
  • Collagen / metabolism
  • Feedback, Physiological*
  • Humans
  • Inflammation / etiology
  • MAP Kinase Signaling System
  • Matrix Metalloproteinase 9 / metabolism*
  • Neutrophil Activation
  • Neutrophils / metabolism
  • Neutrophils / pathology*
  • Oligopeptides / biosynthesis
  • Oligopeptides / physiology
  • Proline / analogs & derivatives
  • Proline / biosynthesis
  • Proline / physiology
  • Receptors, Interleukin-8A / metabolism
  • Receptors, Interleukin-8B / metabolism


  • Chemotactic Factors
  • Oligopeptides
  • Receptors, Interleukin-8A
  • Receptors, Interleukin-8B
  • prolyl-glycyl-proline
  • Collagen
  • Proline
  • Matrix Metalloproteinase 9