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Citations to this article

Proteinase 3 and neutrophil elastase enhance inflammation in mice by inactivating antiinflammatory progranulin
Kai Kessenbrock, … , Reinhard Fässler, Dieter E. Jenne
Kai Kessenbrock, … , Reinhard Fässler, Dieter E. Jenne
Published June 20, 2008
Citation Information: J Clin Invest. 2008;118(7):2438-2447. https://doi.org/10.1172/JCI34694.
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Research Article Inflammation Article has an altmetric score of 8

Proteinase 3 and neutrophil elastase enhance inflammation in mice by inactivating antiinflammatory progranulin

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Abstract

Neutrophil granulocytes form the body’s first line of antibacterial defense, but they also contribute to tissue injury and noninfectious, chronic inflammation. Proteinase 3 (PR3) and neutrophil elastase (NE) are 2 abundant neutrophil serine proteases implicated in antimicrobial defense with overlapping and potentially redundant substrate specificity. Here, we unraveled a cooperative role for PR3 and NE in neutrophil activation and noninfectious inflammation in vivo, which we believe to be novel. Mice lacking both PR3 and NE demonstrated strongly diminished immune complex–mediated (IC-mediated) neutrophil infiltration in vivo as well as reduced activation of isolated neutrophils by ICs in vitro. In contrast, in mice lacking just NE, neutrophil recruitment to ICs was only marginally impaired. The defects in mice lacking both PR3 and NE were directly linked to the accumulation of antiinflammatory progranulin (PGRN). Both PR3 and NE cleaved PGRN in vitro and during neutrophil activation and inflammation in vivo. Local administration of recombinant PGRN potently inhibited neutrophilic inflammation in vivo, demonstrating that PGRN represents a crucial inflammation-suppressing mediator. We conclude that PR3 and NE enhance neutrophil-dependent inflammation by eliminating the local antiinflammatory activity of PGRN. Our results support the use of serine protease inhibitors as antiinflammatory agents.

Authors

Kai Kessenbrock, Leopold Fröhlich, Michael Sixt, Tim Lämmermann, Heiko Pfister, Andrew Bateman, Azzaq Belaaouaj, Johannes Ring, Markus Ollert, Reinhard Fässler, Dieter E. Jenne

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Total citations by year

Year: 2025 2024 2023 2022 2021 2020 2019 2018 2017 2016 2015 2014 2013 2012 2011 2010 2009 Total
Citations: 6 10 11 11 19 17 14 9 10 15 14 16 18 15 16 7 8 216
Citation information
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Citations to this article in year 2018 (9)

Title and authors Publication Year
SAG/RBX2 E3 Ubiquitin Ligase Differentially Regulates Inflammatory Responses of Myeloid Cell Subsets
X Xiong, ND Mathewson, H Li, M Tan, H Fujiwara, H Li, P Reddy, Y Sun
Frontiers in immunology 2018
Gasdermin D Exerts Anti-inflammatory Effects by Promoting Neutrophil Death
H Kambara, F Liu, X Zhang, P Liu, B Bajrami, Y Teng, L Zhao, S Zhou, H Yu, W Zhou, LE Silberstein, T Cheng, M Han, Y Xu, HR Luo
Cell Reports 2018
Murine knockin model for progranulin-deficient frontotemporal dementia with nonsense-mediated mRNA decay
AD Nguyen, TA Nguyen, J Zhang, S Devireddy, P Zhou, AM Karydas, X Xu, BL Miller, F Rigo, SM Ferguson, EJ Huang, TC Walther, RV Farese
Proceedings of the National Academy of Sciences 2018
The lysosomal function of progranulin, a guardian against neurodegeneration
DH Paushter, H Du, T Feng, F Hu
Acta Neuropathologica 2018
Neutrophil elastase in the tumor microenvironment
I Lerman, SR Hammes
Steroids 2018
Early lysosomal maturation deficits in microglia triggers enhanced lysosomal activity in other brain cells of progranulin knockout mice
JK Götzl, AV Colombo, K Fellerer, A Reifschneider, G Werner, S Tahirovic, C Haass, A Capell
Molecular Neurodegeneration 2018
Proteinase 3; a potential target in chronic obstructive pulmonary disease and other chronic inflammatory diseases
H Crisford, E Sapey, RA Stockley
Respiratory Research 2018
Neuroinflammation and blood-brain barrier disruption following traumatic brain injury: Pathophysiology and potential therapeutic targets
S Sulhan, KA Lyon, LA Shapiro, JH Huang
Journal of Neuroscience Research 2018
Myeloperoxidase deficiency attenuates systemic and dietary iron-induced adverse effects
X Xiao, P Saha, BS Yeoh, JA Hipp, V Singh, M Vijay-Kumar
The Journal of Nutritional Biochemistry 2018

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