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Proteinase 3 and neutrophil elastase enhance inflammation in mice by inactivating antiinflammatory progranulin.
J. Clin. Invest. 118, 2438-2447 (2008)
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.
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16.915
4.120
278
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Proteinase 3; neutrophil elastase; progranulin; extravascular basement membrane; CATHEPSIN-G; SERINE-PROTEASE; HOST-DEFENSE; IN-VIVO; CATALYTIC-ACTIVITY; CELL-SURFACE; BONE-MARROW; DEFICIENCY; LEUKOCYTES; EXPRESSION
Language
english
Publication Year
2008
HGF-reported in Year
0
ISSN (print) / ISBN
0021-9738
e-ISSN
1558-8238
Quellenangaben
Volume: 118,
Issue: 7,
Pages: 2438-2447
Publisher
American Society of Clinical Investigation
Reviewing status
Peer reviewed
Institute(s)
Institute of Lung Health and Immunity (LHI)
Institute of Epidemiology (EPI)
Institute of Epidemiology (EPI)
POF-Topic(s)
30202 - Environmental Health
PSP Element(s)
G-521200-001
FE 73991
FE 73991
PubMed ID
18568075
DOI
10.1172/JCI34694
WOS ID
WOS:000257657400012
Erfassungsdatum
2008-12-12