title: Neutrophil-Expressed p21/waf1 Favors Inflammation Resolution in Pseudomonas aeruginosa Infection.
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.
authors.affiliation: 1 Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|2 Department of Pneumology, Cochin Hospital, France.
authors.forename: Clémence
authors.initials: C
authors.lastname: Martin
authors.affiliation: 1 Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|3 Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Paris, France.|4 Centre National de la Recherche Scientifique UMR8104, Paris France.|5 Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'Excellence Inflamex, Paris, France; and.
authors.forename: Delphine
authors.initials: D
authors.lastname: Ohayon
authors.affiliation: 1 Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|3 Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Paris, France.|4 Centre National de la Recherche Scientifique UMR8104, Paris France.|5 Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'Excellence Inflamex, Paris, France; and.
authors.forename: Manal
authors.initials: M
authors.lastname: Alkan
authors.affiliation: 1 Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|3 Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Paris, France.|4 Centre National de la Recherche Scientifique UMR8104, Paris France.|5 Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'Excellence Inflamex, Paris, France; and.
authors.forename: Julie
authors.initials: J
authors.lastname: Mocek
authors.affiliation: 1 Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|3 Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Paris, France.|4 Centre National de la Recherche Scientifique UMR8104, Paris France.|5 Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'Excellence Inflamex, Paris, France; and.
authors.forename: Magali
authors.initials: M
authors.lastname: Pederzoli-Ribeil
authors.affiliation: 1 Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|3 Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Paris, France.|4 Centre National de la Recherche Scientifique UMR8104, Paris France.|5 Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'Excellence Inflamex, Paris, France; and.
authors.forename: Céline
authors.initials: C
authors.lastname: Candalh
authors.affiliation: 1 Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Guiti
authors.initials: G
authors.lastname: Thevenot
authors.affiliation: 1 Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|3 Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Paris, France.|4 Centre National de la Recherche Scientifique UMR8104, Paris France.|5 Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'Excellence Inflamex, Paris, France; and.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Millet
authors.affiliation: 6 Department of Medicine, Section of General Pathology, Verona, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Tamassia
authors.affiliation: 6 Department of Medicine, Section of General Pathology, Verona, Italy.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Cassatella
authors.affiliation: 1 Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|3 Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Paris, France.|4 Centre National de la Recherche Scientifique UMR8104, Paris France.|5 Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'Excellence Inflamex, Paris, France; and.
authors.forename: Nathalie
authors.identifier: 0000-0002-8898-9217
authors.initials: N
authors.lastname: Thieblemont
authors.affiliation: 1 Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|2 Department of Pneumology, Cochin Hospital, France.
authors.forename: Pierre-Régis
authors.initials: PR
authors.lastname: Burgel
authors.affiliation: 1 Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|3 Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Paris, France.|4 Centre National de la Recherche Scientifique UMR8104, Paris France.|5 Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'Excellence Inflamex, Paris, France; and.
authors.forename: Véronique
authors.initials: V
authors.lastname: Witko-Sarsat
mesh_terms: D000293:Adolescent; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D003550:Cystic Fibrosis / Q000150:complications / Q000382:microbiology / Q000473:pathology; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008954:Models, Biological; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D010538:Peritonitis / Q000382:microbiology / Q000473:pathology; D010587:Phagocytosis / Q000187:drug effects; D011014:Pneumonia / Q000150:complications / Q000378:metabolism* / Q000382:microbiology* / Q000473:pathology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011552:Pseudomonas Infections / Q000150:complications / Q000378:metabolism* / Q000382:microbiology*; D011550:Pseudomonas aeruginosa / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015054:Zymosan
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D008070:Lipopolysaccharides; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016179:Granulocyte Colony-Stimulating Factor; D015054:Zymosan
keywords: apoptosis; cystic fibrosis; neutrophil; proliferating cell nuclear antigen