Neutrophils contain prolyl endopeptidase and generate the chemotactic peptide, PGP, from collagen

O’Reilly, Philip; Hardison, Matthew T.; Jackson, Patricia L.; Xu, Xin; Snelgrove, Robert J.; Gaggar, Amit; Galin, F. Shawn; Blalock, J. Edwin

doi:10.1016/j.jneuroim.2009.09.020

Cited by 66 publications

(80 citation statements)

References 30 publications

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“…Neutrophilderived MMP-8 and MMP-9 cleave whole collagen in fragments of 30 to 100 amino acids followed by specific cleavage to release tripeptides, PGP, and its acetylated form, Ac-PGP by the action of propyl endopeptidase (23,63). The multistep pathway in the degradation of collagen, in the presence of MMPs and propyl endopeptidase, was shown in murine models of cigarette smoke (CS)-induced emphysema, and further in vitro studies reported the breakdown of whole collagen to PGP and Ac-PGP (23,63,64). These collagen fragments induce neutrophil chemotaxis through CXC-receptors 1 and 2 on neutrophils, thus precipitating an inflammatory cycle (65).…”

Section: Collagensmentioning

confidence: 99%

Matrix Remodeling in Pulmonary Fibrosis and Emphysema

Kulkarni

O’Reilly

Antony

et al. 2016

Am J Respir Cell Mol Biol

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109

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Pulmonary fibrosis and emphysema are chronic lung diseases characterized by a progressive decline in lung function, resulting in significant morbidity and mortality. A hallmark of these diseases is recurrent or persistent alveolar epithelial injury, typically caused by common environmental exposures such as cigarette smoke. We propose that critical determinants of the outcome of the injury-repair processes that result in fibrosis versus emphysema are mesenchymal cell fate and associated extracellular matrix dynamics. In this review, we explore the concept that regulation of mesenchymal cells under the influence of soluble factors, in particular transforming growth factor-b1, and the extracellular matrix determine the divergent tissue remodeling responses seen in pulmonary fibrosis and emphysema.

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Section: Collagensmentioning

confidence: 99%

Matrix Remodeling in Pulmonary Fibrosis and Emphysema

Kulkarni

O’Reilly

Antony

et al. 2016

Am J Respir Cell Mol Biol

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109

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“…The cleavage of AMC from substrate by PE was detected using a Fluometer Reader at an excitation wavelength of 360 nm and an emission wavelength of 460 nm and compared with a generated standard curve for PE activity (24).…”

Section: Pe Activity Assaymentioning

confidence: 99%

Toll-Like Receptor 4 Engagement Mediates Prolyl Endopeptidase Release from Airway Epithelia via Exosomes

Szul

Bratcher

Fraser³

et al. 2016

Am J Respir Cell Mol Biol

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Proteases are important regulators of pulmonary remodeling and airway inflammation. Recently, we have characterized the enzyme prolyl endopeptidase (PE), a serine peptidase, as a critical protease in the generation of the neutrophil chemoattractant tripeptide Pro-Gly-Pro (PGP) from collagen. However, PE has been characterized as a cytosolic enzyme, and the mechanism mediating PE release extracellularly remains unknown. We examined the role of exosomes derived from airway epithelia as a mechanism for PE release and the potential extracellular signals that regulate the release of these exosomes. We demonstrate a specific regulatory pathway of exosome release from airway epithelia and identify PE as novel exosome cargo. LPS stimulation of airway epithelial cells induces release of PEcontaining exosomes, which is significantly attenuated by small interfering RNA depletion of Toll-like receptor 4 (TLR4). These differences were recapitulated upon intratracheal LPS administration in mice competent versus deficient for TLR4 signaling. Finally, sputum samples from subjects with cystic fibrosis colonized with Pseudomonas aeruginosa demonstrate elevated exosome content and increased PE levels. This TLR4-based mechanism highlights the first report of nonstochastic release of exosomes in the lung and couples TLR4 activation with matrikine generation. The increased quantity of these proteolytic exosomes in the airways of subjects with chronic lung disease highlights a new mechanism of injury and inflammation in the pathogenesis of pulmonary disorders.Keywords: protease; Toll-like receptor 4; exosome; cystic fibrosis; pulmonary Cell-to-cell communication via secreted soluble mediators is critical to the maintenance of cellular homeostasis in complex metazoans. Much of this intercellular communication is regulated through the classical secretory mechanism, in which proteins containing an endoplasmic reticulum (ER)-signaling sequence are actively released via the ER-toGolgi pathway (1). Despite the broad range of proteins entering this pathway, a number of actively secreted proteins lack a signal sequence for release and are released via alternative mechanisms, including exosomes (2).

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“…More recently, proline-glycine-proline (PGP), a tripeptide collagen breakdown product that shares sequence homology with a key motif found in the ELR 1 CXC chemokines and binds to CXCR1 and CXCR2, was found to play an equally important role to ELR 1 CXC chemokines in neutrophil chemotaxis and inflammation (9)(10)(11). PGP is generated in a sequential fashion through the activities of matrix metalloproteinases and the serine protease prolyl endopeptidase on collagen.…”

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confidence: 99%

An Aberrant Leukotriene A₄ Hydrolase–Proline-Glycine-Proline Pathway in the Pathogenesis of Chronic Obstructive Pulmonary Disease

Wells

O’Reilly

Szul

et al. 2014

Am J Respir Crit Care Med

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Rationale: Chronic neutrophilic inflammation is a hallmark in the pathogenesis of chronic obstructive pulmonary disease (COPD) and persists after cigarette smoking has stopped. Mechanisms involved in this ongoing inflammatory response have not been delineated.Objectives: We investigated changes to the leukotriene A 4 hydrolase (LTA 4 H)-proline-glycine-proline (PGP) pathway and chronic inflammation in the development of COPD.Methods: A/J mice were exposed to air or cigarette smoke for 22 weeks followed by bronchoalveolar lavage and lung and cardiac tissue analysis. Two human cohorts were used to analyze changes to the LTA 4 H-PGP pathway in never smokers, control smokers, COPD smokers, and COPD former smokers. PGP/AcPGP and LTA 4 H aminopeptidase activity were detected by mass spectroscopy, LTA 4 H amounts were detected by ELISA, and acrolein was detected by Western blot.Measurements and Main Results: Mice exposed to cigarette smoke developed emphysema with increased PGP, neutrophilic inflammation, and selective inhibition of LTA 4 H aminopeptidase, which ordinarily degrades PGP. We recapitulated these findings in smokers with and without COPD. PGP and AcPGP are closely associated with cigarette smoke use. Once chronic inflammation is established, changes to LTA 4 H aminopeptidase remain, even in the absence of ongoing cigarette use. Acrolein modifies LTA 4 H and inhibits aminopeptidase activity to the same extent as cigarette smoke.Conclusions: These results demonstrate a novel pathway of aberrant regulation of PGP/AcPGP, suggesting this inflammatory pathway may be intimately involved in disease progression in the absence of ongoing cigarette smoke exposure. We highlight a mechanism by which acrolein potentiates neutrophilic inflammation through selective inhibition of LTA 4 H aminopeptidase activity. Clinical trial registered with www.clinicaltrials.gov (NCT 00292552).

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Neutrophils contain prolyl endopeptidase and generate the chemotactic peptide, PGP, from collagen

Cited by 66 publications

References 30 publications

Matrix Remodeling in Pulmonary Fibrosis and Emphysema

Matrix Remodeling in Pulmonary Fibrosis and Emphysema

Toll-Like Receptor 4 Engagement Mediates Prolyl Endopeptidase Release from Airway Epithelia via Exosomes

An Aberrant Leukotriene A₄ Hydrolase–Proline-Glycine-Proline Pathway in the Pathogenesis of Chronic Obstructive Pulmonary Disease

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Neutrophils contain prolyl endopeptidase and generate the chemotactic peptide, PGP, from collagen

Cited by 66 publications

References 30 publications

Matrix Remodeling in Pulmonary Fibrosis and Emphysema

Matrix Remodeling in Pulmonary Fibrosis and Emphysema

Toll-Like Receptor 4 Engagement Mediates Prolyl Endopeptidase Release from Airway Epithelia via Exosomes

An Aberrant Leukotriene A4 Hydrolase–Proline-Glycine-Proline Pathway in the Pathogenesis of Chronic Obstructive Pulmonary Disease

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An Aberrant Leukotriene A₄ Hydrolase–Proline-Glycine-Proline Pathway in the Pathogenesis of Chronic Obstructive Pulmonary Disease