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Am J Respir Cell Mol Biol. 2016 May;54(5):740-50. doi: 10.1165/rcmb.2015-0047OC.

Neutrophil-Expressed p21/waf1 Favors Inflammation Resolution in Pseudomonas aeruginosa Infection.

Martin C1,2, Ohayon D1,3,4,5, Alkan M1,3,4,5, Mocek J1,3,4,5, Pederzoli-Ribeil M1,3,4,5, Candalh C1,3,4,5, Thevenot G1, Millet A1,3,4,5, Tamassia N6, Cassatella MA6, Thieblemont N1,3,4,5, Burgel PR1,2, Witko-Sarsat V1,3,4,5.

Author information

1
1 Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
2
2 Department of Pneumology, Cochin Hospital, France.
3
3 Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Paris, France.
4
4 Centre National de la Recherche Scientifique UMR8104, Paris France.
5
5 Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'Excellence Inflamex, Paris, France; and.
6
6 Department of Medicine, Section of General Pathology, Verona, Italy.

Abstract

Neutrophil-associated inflammation during Pseudomonas aeruginosa lung infection is a determinant of morbidity in cystic fibrosis (CF). Neutrophil apoptosis is a key factor in inflammation resolution and is controlled by cytosolic proliferating cell nuclear antigen (PCNA). p21/Waf1, a cyclin-dependent kinase inhibitor, is a partner of PCNA, and its mRNA is up-regulated in human neutrophils during LPS challenge. We show here that, after 7 days of persistent infection with P. aeruginosa, neutrophilic inflammation was more prominent in p21(-/-) compared with wild-type (WT) mice. Notably, no intrinsic defect in the phagocytosis of apoptotic cells by macrophages was found in p21(-/-) compared with WT mice. Inflammatory cell analysis in peritoneal lavages after zymosan-induced peritonitis showed a significantly increased number of neutrophils at 48 hours in p21(-/-) compared with WT mice. In vitro analysis was consistent with delayed neutrophil apoptosis in p21(-/-) compared with WT mice. Ectopic expression of p21/waf1 in neutrophil-differentiated PLB985 cells potentiated apoptosis and reversed the prosurvival effect of PCNA. In human neutrophils, p21 messenger RNA was induced by TNF-α, granulocyte colony-stimulating factor, and LPS. Neutrophils isolated from patients with CF showed enhanced survival, which was reduced after treatment with a carboxy-peptide derived from the sequence of p21/waf1. Notably, p21/waf1 was detected by immunohistochemistry in neutrophils within lungs from patients with CF. Our data reveal a novel role for p21/waf1 in the resolution of inflammation via its ability to control neutrophil apoptosis. This mechanism may be relevant in the neutrophil-dominated inflammation observed in CF and other chronic inflammatory lung conditions.

KEYWORDS:

apoptosis; cystic fibrosis; neutrophil; proliferating cell nuclear antigen

PMID:
26517580
DOI:
10.1165/rcmb.2015-0047OC
[Indexed for MEDLINE]

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