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J Immunol. 2017 Dec 1;199(11):3914-3924. doi: 10.4049/jimmunol.1601522. Epub 2017 Oct 27.

Transgenic Mice Expressing Human Proteinase 3 Exhibit Sustained Neutrophil-Associated Peritonitis.

Martin KR1,2,3,4, Pederzoli-Ribeil M1,2,3,4, Pacreau E4,5,6, Burgener SS7,8,9, Dahdah A4,5,6, Candalh C1,2,3,4, Lauret E1,2,3, Foretz M1,2,3, Mouthon L1,2,3,4,10, Lucas B1,2,3, Thieblemont N1,2,3,4, Benarafa C7,8, Launay P4,5,6, Witko-Sarsat V11,2,3,4.

Author information

1
INSERM U1016, Institut Cochin, 75014 Paris, France.
2
CNRS-UMR 8104, 75014 Paris, France.
3
Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
4
Center of Excellence, Labex Inflamex, 75014 Paris, France.
5
INSERM U1149, 75018 Paris, France.
6
Université Paris Diderot, Sorbonne Paris Cité, 75018 Paris, France.
7
Institute of Virology and Immunology, 3147 Mittelhäusern, Switzerland.
8
Department of Infectious Diseases and Immunopathology, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland.
9
Graduate School for Cellular and Biomedical Sciences, University of Bern, 3012 Bern, Switzerland; and.
10
Department of Internal Medicine, Cochin Hospital, 75014 Paris, France.
11
INSERM U1016, Institut Cochin, 75014 Paris, France; veronique.witko@inserm.fr.

Abstract

Proteinase 3 (PR3) is a myeloid serine protease expressed in neutrophils, monocytes, and macrophages. PR3 has a number of well-characterized proinflammatory functions, including cleaving and activating chemokines and controlling cell survival and proliferation. When presented on the surface of apoptotic neutrophils, PR3 can disrupt the normal anti-inflammatory reprogramming of macrophages following the phagocytosis of apoptotic cells. To better understand the function of PR3 in vivo, we generated a human PR3 transgenic mouse (hPR3Tg). During zymosan-induced peritonitis, hPR3Tg displayed an increased accumulation of neutrophils within the peritoneal cavity compared with wild-type control mice, with no difference in the recruitment of macrophages or B or T lymphocytes. Mice were also subjected to cecum ligation and puncture, a model used to induce peritoneal inflammation through infection. hPR3Tg displayed decreased survival rates in acute sepsis, associated with increased neutrophil extravasation. The decreased survival and increased neutrophil accumulation were associated with the cleavage of annexin A1, a powerful anti-inflammatory protein known to facilitate the resolution of inflammation. Additionally, neutrophils from hPR3Tg displayed enhanced survival during apoptosis compared with controls, and this may also contribute to the increased accumulation observed during the later stages of inflammation. Taken together, our data suggest that human PR3 plays a proinflammatory role during acute inflammatory responses by affecting neutrophil accumulation, survival, and the resolution of inflammation.

PMID:
29079698
DOI:
10.4049/jimmunol.1601522
[Indexed for MEDLINE]
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