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


RESULTS
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
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.
Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
Xin
X
Xu
Patricia L
PL
Jackson
Scott
S
Tanner
Matthew T
MT
Hardison
Mojtaba
M
Abdul Roda
James Edwin
JE
Blalock
Amit
A
Gaggar
D002630:Chemotactic Factors / Q000502:physiology*; D002908:Chronic Disease; D003094:Collagen / Q000378:metabolism; D025461:Feedback, Physiological; D006801:Humans; D007249:Inflammation / Q000209:etiology; D020935:MAP Kinase Signaling System; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D018375:Neutrophil Activation; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology*; D009842:Oligopeptides / Q000096:biosynthesis / Q000502:physiology; D011392:Proline / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000502:physiology; D023062:Receptors, Interleukin-8A / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000378:metabolism
D002630:Chemotactic Factors; D009842:Oligopeptides; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; C113164:prolyl-glycyl-proline; D003094:Collagen; D011392:Proline; D020780:Matrix Metalloproteinase 9
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