Targeting of cathepsin S reduces cystic fibrosis-like lung disease

Small, D.; Brown, Ryan; Doherty, Declan; Abladey, Anthony; Zhou-Suckow, Zhe; Delaney, Rebecca; Kerrigan, Lauren; Dougan, Caoifa; Borensztajn, Keren; Holsinger, Leslie J.; Booth, R. F. G.; Scott, Christopher J.; López-Campos, Guillermo; Elborn, J.S.; Mall, Marcus; Weldon, Sinéad; Taggart, Clifford C.

doi:10.1183/13993003.01523-2018

Cited by 38 publications

(50 citation statements)

References 41 publications

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“…CTSS is emerging as an important player in early CF lung disease with extracellular CTSS levels correlating significantly with lung function decline and neutrophil recruitment into the airways (47). A recent study, using the βENaC-overexpressing mouse with CF-like lung disease, elucidated roles for CTSS in the in vivo pathogenesis of several key CF pathologies (48). In this study, genetic and pharmacological knockdown of CTSS was associated with a reduction in neutrophil recruitment and amelioration of airway mucus obstruction and lung tissue destruction.…”

Section: The Actions Of Cysteine Proteases In Cfmentioning

confidence: 99%

“…Matrix degradation Serine, cysteine, MMP (52,54,55,70) Cytokine processing Serine, cysteine, MMP (14,18,46,56) Cytokine upregulation Serine, cysteine, MMP (15,48,54,55) PAR activation Serine, cysteine, MMP (48,71) Trans-class protease activation Serine, cysteine (9,12,26,27) Host defence protein degradation (including antiproteases)…”

Section: Functionmentioning

confidence: 99%

“…Serine, cysteine (21-23, 29, 42-45) ENaC activation Serine, cysteine (38,49,50) CFTR degradation Serine (37) Mucus modulation Serine (33)(34)(35)(36)48) Iron liberation Serine (24,25) Definition of abbreviations: MMP = matrix metalloprotease; PAR = protease-activated receptor; ENaC = epithelial sodium channel; CFTR = cystic fibrosis transmembrance conductance regulator.…”

Section: Functionmentioning

confidence: 99%

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Targeting Proteases in Cystic Fibrosis Lung Disease. Paradigms, Progress, and Potential

McKelvey

Weldon

McAuley

et al. 2020

Am J Respir Crit Care Med

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Cystic fibrosis (CF) is the most common life-limiting hereditary condition of Caucasian populations and is characterised by chronic airways inflammation driving progressive structural lung damage. Despite tremendous advances in the treatment of CF and concomitant increased life expectancy for patients, chronic lung disease remains the main cause of morbidity and mortality among CF patients. While universal restoration of cystic fibrosis transmembrane conductance regulator activity remains a future hope, novel therapies aimed at reducing or preventing chronic airways inflammation and progressive structural lung damage are required. It is well-established that proteolytic enzymes are important in the CF lung beyond the basic turnover of proteins and intracellular degradation of pathogens. When secreted, these enzymes play key roles in extracellular substrate modification implicated in important biological processes such as matrix and airway remodelling, goblet cell metaplasia and mucus hypersecretion, immune cell recruitment and dysregulation of epithelial ion channels. Importantly, the burden of proteases in the CF lung is significantly elevated, overwhelming the endogenous antiprotease shield. Indeed, free protease activity has emerged as a major risk factor of the onset and progression of bronchiectasis and lung function decline in patients with CF. Recent research has highlighted the importance of new players such as cathepsin S and matrix metalloprotease-12, as well as the membrane-associated activity of key proteases such as neutrophil elastase on the surface of neutrophils. Here, we review the current knowledge and emerging concepts of the role of host proteases in the pathogenesis of CF lung disease and their potential as therapeutic targets.

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Section: The Actions Of Cysteine Proteases In Cfmentioning

confidence: 99%

Section: Functionmentioning

confidence: 99%

Section: Functionmentioning

confidence: 99%

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Targeting Proteases in Cystic Fibrosis Lung Disease. Paradigms, Progress, and Potential

McKelvey

Weldon

McAuley

et al. 2020

Am J Respir Crit Care Med

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“…Finally, we show that lack of IL-1R reduced emphysema-like lung damage, as determined from measurements of MLI and DI in juvenile Scnn1b-Tg/Il1r1 -/mice ( Figure 5A-C). In previous studies we demonstrated that neutrophil elastase (NE), macrophage elastase (matrix metalloproteinase 12 ) and cathepsin S released from activated neutrophils and macrophages in mucostatic airways, are major contributors to structural lung damage in Scnn1b-Tg mice (28,35,36). While airway neutrophils were also reduced in Scnn1b-Tg/Il1r1 -/mice ( Figure 1C), it is important to note that Scnn1b-Tg/NE -/presented with residual emphysema suggesting that other factors may contribute to emphysema formation in this model.…”

Section: Discussionmentioning

confidence: 99%

Lack of IL-1 Receptor Signaling Reduces Spontaneous Airway Eosinophilia in Juvenile Mice with Muco-Obstructive Lung Disease

Brown

Paulsen

Schmidt

et al. 2020

Am J Respir Cell Mol Biol

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Previous studies demonstrated spontaneous type 2 airway inflammation with eosinophilia juvenile Scnn1b-Tg mice with muco-obstructive lung disease. Interleukin-1 receptor (IL-1R) signaling has been implicated in allergen-driven airways disease, however, its role in eosinophilic inflammation in mucoobstructive lung disease remains unknown. In this study, we examined the role of IL-1R signaling in the development of airway eosinophilia and type 2 inflammation in juvenile Scnn1b-Tg mice. We determined effects of genetic deletion of Il1r1 on eosinophil counts, transcript levels of key type 2 cytokines, markers of eosinophil activation and apoptosis, and tissue morphology in lungs of Scnn1b-Tg mice at different time points during neonatal development. Further, we measured endothelial surface expression of intercellular adhesion molecule 1 (ICAM-1), an integrin involved in eosinophil transendothelial migration, and determined effects of eosinophil depletion using an anti-IL-5 antibody on lung morphology. Lack of IL-1R reduced airway eosinophilia and structural lung damage, but did not reduce levels of type 2 cytokines and associated eosinophil activation in Scnn1b-Tg mice. Structural lung damage in Scnn1b-Tg mice was also reduced by eosinophil depletion. Lack of IL-1R was associated with reduced expression of ICAM-1 on lung endothelial cells and reduced eosinophil counts in lungs from Scnn1b-Tg mice. We conclude that IL-1R signaling is implicated in airway eosinophilia independent of type 2 cytokines in juvenile Scnn1b-Tg mice. Our data suggest that IL-1R signaling may be relevant in the pathogenesis of eosinophilic airway inflammation in muco-obstructive lung diseases, which may, in part, be mediated by ICAM-1 dependent transmigration of eosinophils into the lungs.

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“…In addition, instillation of CatS into the lungs of wild-type mice results in inflammation, lung remodelling, and upregulation of mucin expression, while CatS inhibition leads to a reduction in airway inflammation and mucin expression. Taken together, it has been proposed that CatS plays a critical role in the pathogenesis of cystic fibrosis and some CF-like lung diseases, highlighting CatS as a valuable therapeutic target [57]. Nevertheless, cathepsins B, H, K, L, and S levels remain unchanged in the sputum of CF patients infected or not by Pseudomonas aeruginosa, suggesting that they are not markers of bacterial infection [58].…”

Section: Cysteine Cathepsins In Pulmonary Diseasesmentioning

confidence: 99%

Regulation of the Proteolytic Activity of Cysteine Cathepsins by Oxidants

Lalmanach

Saidi

Bigot

et al. 2020

IJMS

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Besides their primary involvement in the recycling and degradation of proteins in endo-lysosomal compartments and also in specialized biological functions, cysteine cathepsins are pivotal proteolytic contributors of various deleterious diseases. While the molecular mechanisms of regulation via their natural inhibitors have been exhaustively studied, less is currently known about how their enzymatic activity is modulated during the redox imbalance associated with oxidative stress and their exposure resistance to oxidants. More specifically, there is only patchy information on the regulation of lung cysteine cathepsins, while the respiratory system is directly exposed to countless exogenous oxidants contained in dust, tobacco, combustion fumes, and industrial or domestic particles. Papain-like enzymes (clan CA, family C1, subfamily C1A) encompass a conserved catalytic thiolate-imidazolium pair (Cys25-His159) in their active site. Although the sulfhydryl group (with a low acidic pKa) is a potent nucleophile highly susceptible to chemical modifications, some cysteine cathepsins reveal an unanticipated resistance to oxidative stress. Besides an introductory chapter and peculiar attention to lung cysteine cathepsins, the purpose of this review is to afford a concise update of the current knowledge on molecular mechanisms associated with the regulation of cysteine cathepsins by redox balance and by oxidants (e.g., Michael acceptors, reactive oxygen, and nitrogen species).

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Targeting of cathepsin S reduces cystic fibrosis-like lung disease

Cited by 38 publications

References 41 publications

Targeting Proteases in Cystic Fibrosis Lung Disease. Paradigms, Progress, and Potential

Targeting Proteases in Cystic Fibrosis Lung Disease. Paradigms, Progress, and Potential

Lack of IL-1 Receptor Signaling Reduces Spontaneous Airway Eosinophilia in Juvenile Mice with Muco-Obstructive Lung Disease

Regulation of the Proteolytic Activity of Cysteine Cathepsins by Oxidants

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