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Cathepsin C from extracellular histone-induced M1 alveolar macrophages promotes NETosis during lung ischemia-reperfusion injury.
- Source :
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Redox biology [Redox Biol] 2024 Aug; Vol. 74, pp. 103231. Date of Electronic Publication: 2024 Jun 06. - Publication Year :
- 2024
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Abstract
- Primary graft dysfunction (PGD) is a severe form of acute lung injury resulting from lung ischemia/reperfusion injury (I/R) in lung transplantation (LTx), associated with elevated post-transplant morbidity and mortality rates. Neutrophils infiltrating during reperfusion are identified as pivotal contributors to lung I/R injury by releasing excessive neutrophil extracellular traps (NETs) via NETosis. While alveolar macrophages (AMs) are involved in regulating neutrophil chemotaxis and infiltration, their role in NETosis during lung I/R remains inadequately elucidated. Extracellular histones constitute the main structure of NETs and can activate AMs. In this study, we confirmed the significant involvement of extracellular histone-induced M1 phenotype of AMs (M1-AMs) in driving NETosis during lung I/R. Using secretome analysis, public protein databases, and transwell co-culture models of AMs and neutrophils, we identified Cathepsin C (CTSC) derived from AMs as a major mediator in NETosis. Further elucidating the molecular mechanisms, we found that CTSC induced NETosis through a pathway dependent on NADPH oxidase-mediated production of reactive oxygen species (ROS). CTSC could significantly activate p38 MAPK, resulting in the phosphorylation of the NADPH oxidase subunit p47 <superscript>phox</superscript> , thereby facilitating the trafficking of cytoplasmic subunits to the cell membrane and activating NADPH oxidase. Moreover, CTSC up-regulated and activated its substrate membrane proteinase 3 (mPR3), resulting in an increased release of NETosis-related inflammatory factors. Inhibiting CTSC revealed great potential in mitigating NETosis-related injury during lung I/R. These findings suggests that CTSC from AMs may be a crucial factor in mediating NETosis during lung I/R, and targeting CTSC inhition may represent a novel intervention for PGD in LTx.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Mice
NADPH Oxidases metabolism
Male
Humans
Lung metabolism
Lung pathology
Acute Lung Injury metabolism
Acute Lung Injury pathology
Acute Lung Injury etiology
p38 Mitogen-Activated Protein Kinases metabolism
Primary Graft Dysfunction metabolism
Primary Graft Dysfunction pathology
Reperfusion Injury metabolism
Reperfusion Injury pathology
Macrophages, Alveolar metabolism
Extracellular Traps metabolism
Histones metabolism
Neutrophils metabolism
Cathepsin C metabolism
Cathepsin C genetics
Reactive Oxygen Species metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2213-2317
- Volume :
- 74
- Database :
- MEDLINE
- Journal :
- Redox biology
- Publication Type :
- Academic Journal
- Accession number :
- 38861835
- Full Text :
- https://doi.org/10.1016/j.redox.2024.103231