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.
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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FEBS Letters | 2011 |
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LD Muynck, PV Damme |
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H Toh, BP Chitramuthu, HP Bennett, A Bateman |
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P Bossù, F Salani, A Alberici, S Archetti, G Bellelli, D Galimberti, E Scarpini, G Spalletta, C Caltagirone, A Padovani, B Borroni |
Journal of Neuroinflammation | 2011 |
Mucosal Progranulin expression is induced by H. pylori, but independent of Secretory Leukocyte Protease Inhibitor (SLPI) expression
T Wex, D Kuester, C Schönberg, D Schindele, G Treiber, P Malfertheiner |
BMC Gastroenterology | 2011 |
The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice
W Tang, Y Lu, QY Tian, Y Zhang, FJ Guo, GY Liu, NM Syed, Y Lai, EA Lin, L Kong, J Su, F Yin, AH Ding, A Zanin-Zhorov, ML Dustin, J Tao, J Craft, Z Yin, JQ Feng, SB Abramson, XP Yu, C Liu |
Science (New York, N.Y.) | 2011 |
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LY Al-Ayadhi, GA Mostafa |
Journal of Neuroinflammation | 2011 |
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C Reardon, M Lechmann, A Brüstle, MG Gareau, N Shuman, D Philpott, SF Ziegler, TW Mak |
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Progranulin Is a Chemoattractant for Microglia and Stimulates Their Endocytic Activity
F Pickford, J Marcus, LM Camargo, Q Xiao, D Graham, JR Mo, M Burkhardt, V Kulkarni, J Crispino, H Hering, M Hutton |
The American Journal of Pathology | 2011 |
Extracellular progranulin protects cortical neurons from toxic insults by activating survival signaling
J Xu, M Xilouri, J Bruban, J Shioi, Z Shao, I Papazoglou, K Vekrellis, NK Robakis |
Neurobiology of Aging | 2011 |
Potential mechanisms of progranulin-deficient FTLD
ME Ward, BL Miller |
Journal of molecular neuroscience : MN | 2011 |