Neutrophil Elastase, Proteinase 3, and Cathepsin G as Therapeutic Targets in Human Diseases

Korkmaz, Brice; Horwitz, Marshall S.; Jenne, Dieter E.; Gauthier, Francis

doi:10.1124/pr.110.002733

Cited by 709 publications

(795 citation statements)

References 441 publications

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“…As such, it has unsurprisingly been implicated in various human diseases including congenital neutropenia,32 chronic obstructive pulmonary disease, cystic fibrosis, acute lung injury, and acute respiratory distress syndrome 1, 2. Studies have also reported that elevated levels of plasma NE were observed in patients with various cardiovascular diseases,33, 34, 35, 36 and NE mRNA and protein were both detectable within human atherosclerotic plaques 7.…”

Section: Discussionmentioning

confidence: 99%

“…As a major component of neutrophil's armory, NE has been primarily linked to the nonoxidative pathway of intracellular and extracellular pathogen destruction 1. Specifically, it has been suggested that NE acts intracellularly within phagolysosomes to digest phagocytosed microorganisms in combination with microbicidal peptides and the membrane‐associated NADPH oxidase system, which produces reactive oxygen metabolites to destroy ingested pathogens 2. The antimicrobial role of NE in infection and host defense has been demonstrated in a gene target deletion study where NE‐deficient mice were found to exhibit defective microbicidal activity and were more susceptible than their wild‐type (WT) control littermates to sepsis and death following intraperitoneal challenge with Gram‐negative bacteria 3.…”

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confidence: 99%

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Genetic and Pharmacologic Inhibition of the Neutrophil Elastase Inhibits Experimental Atherosclerosis

Wen

Chen

et al. 2018

JAHA

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BackgroundTo investigate whether neutrophil elastase (NE) plays a causal role in atherosclerosis, and the molecular mechanisms involved.Methods and Results NE genetic–deficient mice (Apolipoprotein E−/−/NE −/− mice), bone marrow transplantation, and a specific NE inhibitor (GW311616A) were employed in this study to establish the causal role of NE in atherosclerosis. Aortic expression of NE mRNA and plasma NE activity was significantly increased in high‐fat diet (HFD)–fed wild‐type (WT) (Apolipoprotein E−/−) mice but, as expected, not in NE‐deficient mice. Selective NE knockout markedly reduced HFD‐induced atherosclerosis and significantly increased indicators of atherosclerotic plaque stability. While plasma lipid profiles were not affected by NE deficiency, decreased levels of circulating proinflammatory cytokines and inflammatory monocytes (Ly6Chi/CD11b+) were observed in NE‐deficient mice fed with an HFD for 12 weeks as compared with WT. Bone marrow reconstitution of WT mice with NE −/− bone marrow cells significantly reduced HFD‐induced atherosclerosis, while bone marrow reconstitution of NE −/− mice with WT bone marrow cells restored the pathological features of atherosclerotic plaques induced by HFD in NE‐deficient mice. In line with these findings, pharmacological inhibition of NE in WT mice through oral administration of NE inhibitor GW311616A also significantly reduced atherosclerosis. Mechanistically, we demonstrated that NE promotes foam cell formation by increasing ATP‐binding cassette transporter ABCA1 protein degradation and inhibiting macrophage cholesterol efflux.ConclusionsWe outlined a pathogenic role for NE in foam cell formation and atherosclerosis development. Consequently, inhibition of NE may represent a potential therapeutic approach to treating cardiovascular disease.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Genetic and Pharmacologic Inhibition of the Neutrophil Elastase Inhibits Experimental Atherosclerosis

Wen

Chen

et al. 2018

JAHA

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“…In the presence of a competitive inhibitor (I), the MichaelisMenten kinetics are given by equation (2). Initial enzyme reaction rates (v 0 ) were determined as a function of the substrate concentration in the absence and presence of five different inhibitor concentrations ([I]).…”

Section: Methodsmentioning

confidence: 99%

“…During inflammation, NE is released into the extracellular space, where its activity is tightly contained by alpha-1-antitrypsin (AAT), an abundant neutrophil elastase inhibitor of blood plasma. Intratracheal instillation of human neutrophil elastase and porcine pancreas elastase into an animal model lead to emphysema and was the first indication that an imbalance between neutrophil elastase and AAT is an important pathogenic mechanism for lung injury 1,2 . Both environmental factors like cigarette smoke or air pollution and genetic factors can lead to a disruption of the protease-antiprotease balance [3][4][5] .…”

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confidence: 99%

Autoprocessing of neutrophil elastase near its active site reduces the efficiency of natural and synthetic elastase inhibitors

et al. 2015

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An imbalance between neutrophil-derived proteases and extracellular inhibitors is widely regarded as an important pathogenic mechanism for lung injury. Despite intense efforts over the last three decades, attempts to develop small-molecule inhibitors for neutrophil elastase have failed in the clinic. Here we discover an intrinsic self-cleaving property of mouse neutrophil elastase that interferes with the action of elastase inhibitors. We show that conversion of the single-chain (sc) into a two-chain (tc) neutrophil elastase by self-cleavage near its S1 pocket altered substrate activity and impaired both inhibition by endogenous a-1-antitrypsin and synthetic small molecules. Our data indicate that autoconversion of neutrophil elastase decreases the inhibitory efficacy of natural a-1-antitrypsin and smallmolecule inhibitors, while retaining its pathological potential in an experimental mouse model. The so-far overlooked occurrence and properties of a naturally occurring tc-form of neutrophil elastase necessitates the redesign of small-molecule inhibitors that target the sc-form as well as the tc-form of neutrophil elastase.

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“…In this case, neutrophil azurophilic granules contain four enzymatically active serine proteases which include neutrophil elastase, cathepsin G, proteinase-3, and neutrophil serine protease-4 along with a single nonactive member, named azurocidin. [33][34][35] Interestingly, while azurocidin also contains point mutations that render its catalytic triad inactive, 36 a body of literature has also reported chemotactic and immunoregulatory activity associated with release of azurocidin during inflammatory events (reviewed in Ref. 35).…”

Section: Discussionmentioning

confidence: 99%

NlpC/P60 domain‐containing proteins of Mycobacterium avium subspecies paratuberculosis that differentially bind and hydrolyze peptidoglycan

et al. 2016

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A subset of proteins containing NlpC/P60 domains are bacterial peptidoglycan hydrolases that cleave noncanonical peptide linkages and contribute to cell wall remodeling as well as cell separation during late stages of division. Some of these proteins have been shown to cleave peptidoglycan in Mycobacterium tuberculosis and play a role in Mycobacterium marinum virulence of zebra fish; however, there are still significant knowledge gaps concerning the molecular function of these proteins in Mycobacterium avium subspecies paratuberculosis (MAP). The MAP genome sequence encodes five NlpC/P60 domain-containing proteins. We describe atomic resolution crystal structures of two such MAP proteins, MAP_1272c and MAP_1204. These crystal structures, combined with functional assays to measure peptidoglycan cleavage activity, led to the observation that MAP_1272c does not have a functional catalytic core for peptidoglycan hydrolysis. Furthermore, the structure and sequence of MAP_1272c demonstrate that the catalytic residues normally required for hydrolysis are absent, and the protein does not bind peptidoglycan as efficiently as MAP_1204. While the NlpC/P60 catalytic triad is present in MAP_1204, changing the catalytic cysteine-155 residue to a serine significantly diminished catalytic activity, but did not affect binding to peptidoglycan. Collectively, these findings suggest a broader functional repertoire for NlpC/P60 domain-containing proteins than simply hydrolases. Keywords: Mycobacterium; Johne's disease; crystal structure; peptidoglycan; proteins; antigens; paratuberculosis Additional Supporting Information may be found in the online version of this article.Importance: Johne's disease in ruminant livestock is caused by the bacterium Mycobacterium avium subspecies paratuberculosis. This research describes the functional aspects of two proteins that show promise in a subunit vaccine for Johne's disease. Through crystal structure determination and amino acid modification, we demonstrate that although both proteins have a similar structure, one of them lacked hydrolytic activity on peptidoglycan. We show that a specific amino acid is likely responsible for this lack of hydrolytic activity.

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Neutrophil Elastase, Proteinase 3, and Cathepsin G as Therapeutic Targets in Human Diseases

Cited by 709 publications

References 441 publications

Genetic and Pharmacologic Inhibition of the Neutrophil Elastase Inhibits Experimental Atherosclerosis

Genetic and Pharmacologic Inhibition of the Neutrophil Elastase Inhibits Experimental Atherosclerosis

Autoprocessing of neutrophil elastase near its active site reduces the efficiency of natural and synthetic elastase inhibitors

NlpC/P60 domain‐containing proteins of Mycobacterium avium subspecies paratuberculosis that differentially bind and hydrolyze peptidoglycan

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