---
OA_type: free access
_id: '3943'
abstract:
- lang: eng
  text: 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.
article_processing_charge: No
article_type: original
author:
- first_name: Kai
  full_name: Kessenbrock, Kai
  last_name: Kessenbrock
- first_name: Leopold
  full_name: Fröhlich, Leopold
  last_name: Fröhlich
- first_name: Michael K
  full_name: Sixt, Michael K
  id: 41E9FBEA-F248-11E8-B48F-1D18A9856A87
  last_name: Sixt
  orcid: 0000-0002-6620-9179
- first_name: Tim
  full_name: Lämmermann, Tim
  last_name: Lämmermann
- first_name: Heiko
  full_name: Pfister, Heiko
  last_name: Pfister
- first_name: Andrew
  full_name: Bateman, Andrew
  last_name: Bateman
- first_name: Azzaq
  full_name: Belaaouaj, Azzaq
  last_name: Belaaouaj
- first_name: Johannes
  full_name: Ring, Johannes
  last_name: Ring
- first_name: Markus
  full_name: Ollert, Markus
  last_name: Ollert
- first_name: Reinhard
  full_name: Fässler, Reinhard
  last_name: Fässler
- first_name: Dieter
  full_name: Jenne, Dieter
  last_name: Jenne
citation:
  ama: Kessenbrock K, Fröhlich L, Sixt MK, et al. Proteinase 3 and neutrophil elastase
    enhance inflammation in mice by inactivating antiinflammatory progranulin. <i>The
    Journal of Clinical Investigation</i>. 2008;118(7):2438-2447. doi:<a href="https://doi.org/10.1172/JCI34694">10.1172/JCI34694</a>
  apa: Kessenbrock, K., Fröhlich, L., Sixt, M. K., Lämmermann, T., Pfister, H., Bateman,
    A., … Jenne, D. (2008). Proteinase 3 and neutrophil elastase enhance inflammation
    in mice by inactivating antiinflammatory progranulin. <i>The Journal of Clinical
    Investigation</i>. American Society for Clinical Investigation. <a href="https://doi.org/10.1172/JCI34694">https://doi.org/10.1172/JCI34694</a>
  chicago: Kessenbrock, Kai, Leopold Fröhlich, Michael K Sixt, Tim Lämmermann, Heiko
    Pfister, Andrew Bateman, Azzaq Belaaouaj, et al. “Proteinase 3 and Neutrophil
    Elastase Enhance Inflammation in Mice by Inactivating Antiinflammatory Progranulin.”
    <i>The Journal of Clinical Investigation</i>. American Society for Clinical Investigation,
    2008. <a href="https://doi.org/10.1172/JCI34694">https://doi.org/10.1172/JCI34694</a>.
  ieee: K. Kessenbrock <i>et al.</i>, “Proteinase 3 and neutrophil elastase enhance
    inflammation in mice by inactivating antiinflammatory progranulin,” <i>The Journal
    of Clinical Investigation</i>, vol. 118, no. 7. American Society for Clinical
    Investigation, pp. 2438–2447, 2008.
  ista: Kessenbrock K, Fröhlich L, Sixt MK, Lämmermann T, Pfister H, Bateman A, Belaaouaj
    A, Ring J, Ollert M, Fässler R, Jenne D. 2008. Proteinase 3 and neutrophil elastase
    enhance inflammation in mice by inactivating antiinflammatory progranulin. The
    Journal of Clinical Investigation. 118(7), 2438–2447.
  mla: Kessenbrock, Kai, et al. “Proteinase 3 and Neutrophil Elastase Enhance Inflammation
    in Mice by Inactivating Antiinflammatory Progranulin.” <i>The Journal of Clinical
    Investigation</i>, vol. 118, no. 7, American Society for Clinical Investigation,
    2008, pp. 2438–47, doi:<a href="https://doi.org/10.1172/JCI34694">10.1172/JCI34694</a>.
  short: K. Kessenbrock, L. Fröhlich, M.K. Sixt, T. Lämmermann, H. Pfister, A. Bateman,
    A. Belaaouaj, J. Ring, M. Ollert, R. Fässler, D. Jenne, The Journal of Clinical
    Investigation 118 (2008) 2438–2447.
date_created: 2018-12-11T12:06:01Z
date_published: 2008-06-20T00:00:00Z
date_updated: 2026-05-29T09:19:48Z
day: '20'
doi: 10.1172/JCI34694
extern: '1'
external_id:
  pmid:
  - '18568075'
intvolume: '       118'
issue: '7'
language:
- iso: eng
month: '06'
oa_version: None
page: 2438 - 2447
pmid: 1
publication: The Journal of Clinical Investigation
publication_identifier:
  eissn:
  - 1558-8238
  issn:
  - 0021-9738
publication_status: published
publisher: American Society for Clinical Investigation
publist_id: '2183'
status: public
title: Proteinase 3 and neutrophil elastase enhance inflammation in mice by inactivating
  antiinflammatory progranulin
type: journal_article
user_id: 317138e5-6ab7-11ef-aa6d-ffef3953e345
volume: 118
year: '2008'
...