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

Abstract

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.

• Authors: Xin Xu, Patricia L Jackson, Scott Tanner, Matthew T Hardison, Mojtaba Abdul Roda, James Edwin Blalock, Amit Gaggar
• Journal: PloS one (PLoS One) Vol. 6 Issue 1 Pg. e15781 (Jan 13 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 21249198 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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