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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

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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Figure 1

Generation and characterization of Prtn3–/–Ela2–/– mice.

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Generation and characterization of Prtn3–/–Ela2–/– mice.
   
(A) Souther...
(A) Southern blot showing the WT (+/+) 11.5-kb band of the nontargeted allele and the presence of an additional 7.5-kb band in a heterozygous (+/–) PR3/NE-targeted embryonic stem cell clone. (B) RT-PCR revealed the complete lack of mouse PR3 (mPR3; 437 bp) and mouse NE (743 bp) transcripts in bone marrow cells from Prtn3–/–Ela2–/– mice (–/–), while expression of β-actin (699 bp) was normal. (C) Casein zymography showed prominent casein degradative activity at 27 kDa in WT neutrophil lysates, while intermediate degradation by heterozygous lines and no degradation by Prtn3–/–Ela2–/– lines was found at this size. M, marker. (D) Western blot analysis of granule enzyme expression in bone marrow–derived neutrophils. In Prtn3–/–Ela2–/– neutrophils, no signals for PR3 and NE were detected, while CG (~26 kDa), MPO (~59 kDa), and a smaller degradation product of MPO were detected at the same levels as in WT neutrophils. (E) Microscopic analysis of H&E-stained blood smears revealed normal granulocyte morphology in Prtn3–/–Ela2–/– mice, with a polymorphic nucleus (dark blue) identical to that of WT neutrophils. Original magnification, ×20. (F) Flow cytometry of peripheral blood with gating on Gr-1hiCD11b+ showed regular neutrophil populations (boxed regions) in Prtn3–/–Ela2–/– mice. Plots are representative of data obtained from 3 mice per group. Percentages denote percent cells in the boxed regions.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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