title: Natural killer cells induce eosinophil activation and apoptosis.
abstract: Eosinophils are potent inflammatory cells with numerous immune functions, including antigen presentation and exacerbation of inflammatory responses through their capacity to release a range of largely preformed cytokines and lipid mediators. Thus, timely regulation of eosinophil activation and apoptosis is crucial to develop beneficial immune response and to avoid tissue damage and induce resolution of inflammation. Natural Killer (NK) cells have been reported to influence innate and adaptive immune responses by multiple mechanisms including cytotoxicity against other immune cells. In this study, we analyzed the effect of the interaction between NK cells and eosinophils. Co-culture experiments revealed that human NK cells could trigger autologous eosinophil activation, as shown by up-regulation of CD69 and down-regulation of CD62L, as well as degranulation, evidenced by increased CD63 surface expression, secretion of eosinophil cationic protein (ECP) and eosinophil derived neurotoxin (EDN). Moreover, NK cells significantly and dose dependently increased eosinophil apoptosis as shown by annexin V and propidium iodide (PI) staining. Direct contact was necessary for eosinophil degranulation and apoptosis. Increased expression of phosphorylated extracellular signal-regulated kinase (ERK) in cocultured eosinophils and inhibition of eosinophil CD63 expression by pharmacologic inhibitors suggest that MAPK and PI3K pathways are involved in NK cell-induced eosinophil degranulation. Finally, we showed that NK cells increased reactive oxygen species (ROS) expression by eosinophils in co-culture and that mitochondrial inhibitors (rotenone and antimycin) partially diminished NK cell-induced eosinophil apoptosis, suggesting the implication of mitochondrial ROS in NK cell-induced eosinophil apoptosis. Pan-caspase inhibitor (ZVAD-FMK) only slightly decreased eosinophil apoptosis in coculture. Altogether, our results suggest that NK cells regulate eosinophil functions by inducing their activation and their apoptosis.
authors.affiliation: Pulmonary Immunity, Institut National de la Santé Et de la Recherche Médicale, Lille, France; Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France; CNRS UMR 8204, Lille, France; Univ Lille Nord de France, Lille, France.
authors.forename: Ali
authors.initials: A
authors.lastname: Awad
authors.affiliation: Pulmonary Immunity, Institut National de la Santé Et de la Recherche Médicale, Lille, France; Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France; CNRS UMR 8204, Lille, France; Univ Lille Nord de France, Lille, France.
authors.forename: Hanane
authors.initials: H
authors.lastname: Yassine
authors.affiliation: Pulmonary Immunity, Institut National de la Santé Et de la Recherche Médicale, Lille, France; Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France; CNRS UMR 8204, Lille, France; Univ Lille Nord de France, Lille, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Barrier
authors.affiliation: Pulmonary Immunity, Institut National de la Santé Et de la Recherche Médicale, Lille, France; Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France; CNRS UMR 8204, Lille, France; Univ Lille Nord de France, Lille, France.
authors.forename: Han
authors.initials: H
authors.lastname: Vorng
authors.affiliation: Pulmonary Immunity, Institut National de la Santé Et de la Recherche Médicale, Lille, France; Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France; CNRS UMR 8204, Lille, France; Univ Lille Nord de France, Lille, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Marquillies
authors.affiliation: Pulmonary Immunity, Institut National de la Santé Et de la Recherche Médicale, Lille, France; Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France; CNRS UMR 8204, Lille, France; Univ Lille Nord de France, Lille, France; Clinique des Maladies Respiratoires et Centre Hospitalier Régional et Universitaire de Lille, Lille, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Tsicopoulos
authors.affiliation: Pulmonary Immunity, Institut National de la Santé Et de la Recherche Médicale, Lille, France; Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France; CNRS UMR 8204, Lille, France; Univ Lille Nord de France, Lille, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Duez
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D002450:Cell Communication / Q000187:drug effects; D015550:Cell Degranulation / Q000187:drug effects; D004579:Electron Transport / Q000187:drug effects; D047150:Eosinophil Cationic Protein / Q000378:metabolism; D047208:Eosinophil-Derived Neurotoxin / Q000378:metabolism; D004804:Eosinophils / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D005557:Formaldehyde / Q000494:pharmacology; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology* / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011108:Polymers / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012995:Solubility
chemical_list: D011108:Polymers; D017382:Reactive Oxygen Species; D005557:Formaldehyde; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; D047208:Eosinophil-Derived Neurotoxin; D047150:Eosinophil Cationic Protein; C003043:paraform
references.citation: Nat Rev Immunol. 2008 Sep;8(9):713-25
references.pmid: 19172692
references.citation: J Immunol. 1996 May 15;156(10):3678-86
references.pmid: 8621902
references.citation: J Immunol. 2004 Sep 15;173(6):3716-24
references.pmid: 15356117
references.citation: J Immunol Methods. 2004 Nov;294(1-2):15-22
references.pmid: 15604012
references.citation: J Immunol. 2011 Jun 1;186(11):6129-35
references.pmid: 21515793
references.citation: Blood. 2005 Jul 15;106(2):566-71
references.pmid: 15784725
references.citation: J Immunol. 2001 Dec 1;167(11):6132-9
references.pmid: 11714772
references.citation: J Immunol. 2009 Jan 15;182(2):1011-20
references.pmid: 19124744
references.citation: J Biol Chem. 2006 Sep 15;281(37):27190-6
references.pmid: 16831868
references.citation: J Immunol. 2009 Oct 15;183(8):5023-31
references.pmid: 19794066
references.citation: Sci Transl Med. 2013 Feb 27;5(174):174ra26
references.pmid: 23447017
references.citation: Eur J Immunol. 2000 Mar;30(3):787-93
references.pmid: 10741393
references.citation: J Exp Med. 1999 Feb 1;189(3):553-62
references.pmid: 9927517
references.citation: Blood. 2010 Aug 26;116(8):1308-16
references.pmid: 20501895
references.citation: J Immunol. 2012 Feb 15;188(4):1668-74
references.pmid: 22231698
references.citation: Annu Rev Immunol. 2006;24:147-74
references.pmid: 16551246
references.citation: Blood. 2005 Jul 15;106(2):609-16
references.pmid: 15802534
references.citation: Blood. 2008 Aug 1;112(3):461-9
references.pmid: 18650461
references.citation: Front Immunol. 2013 Mar 06;4:47
references.pmid: 23508471
references.citation: Blood. 2002 Jun 1;99(11):4039-47
references.pmid: 12010805
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):3017-22
references.pmid: 18287025
references.citation: Blood. 1992 Jun 15;79(12):3101-9
references.pmid: 1596561
references.citation: Annu Rev Immunol. 2005;23:225-74
references.pmid: 15771571
references.citation: J Allergy Clin Immunol. 2013 Aug;132(2):437-45
references.pmid: 23684072
references.citation: Nat Rev Immunol. 2003 May;3(5):361-70
references.pmid: 12766758
references.citation: J Immunol. 1996 Aug 1;157(3):1117-26
references.pmid: 8757616
references.citation: J Leukoc Biol. 1990 May;47(5):440-8
references.pmid: 2159514
references.citation: J Immunol. 2000 Aug 15;165(4):1782-9
references.pmid: 10925255
references.citation: J Leukoc Biol. 2007 Jan;81(1):92-9
references.pmid: 16997859
references.citation: J Immunol. 1999 Nov 15;163(10):5358-66
references.pmid: 10553060
references.citation: APMIS. 2011 Feb;119(2):119-26
references.pmid: 21208279
references.citation: Immunity. 1996 Jun;4(6):573-81
references.pmid: 8673704
references.citation: J Exp Med. 2002 Feb 4;195(3):343-51
references.pmid: 11828009
references.citation: J Exp Med. 2002 Feb 4;195(3):335-41
references.pmid: 11828008
references.citation: Adv Immunol. 1986;39:177-253
references.pmid: 3538819
references.citation: Annu Rev Immunol. 2001;19:197-223
references.pmid: 11244035
references.citation: J Immunol. 2004 Nov 15;173(10):6418-26
references.pmid: 15528382
references.citation: Mediators Inflamm. 2011;2011:373589
references.pmid: 21765616
references.citation: Trends Immunol. 2004 Jan;25(1):47-52
references.pmid: 14698284
references.citation: J Allergy Clin Immunol. 1997 Oct;100(4):536-43
references.pmid: 9338549
references.citation: J Immunol. 2000 Aug 15;165(4):2198-204
references.pmid: 10925307
references.citation: J Immunol. 2004 Sep 15;173(6):3653-9
references.pmid: 15356110
references.citation: Immunol Rev. 2007 Dec;220:169-82
references.pmid: 17979846
references.citation: Clin Exp Allergy. 2008 May;38(5):709-50
references.pmid: 18384431
references.citation: J Orthop Res. 2010 Aug;28(8):1057-63
references.pmid: 20108345
references.citation: J Biol Chem. 2003 Sep 19;278(38):36027-31
references.pmid: 12840017
references.citation: Scand J Immunol. 2010 Aug;72(2):118-27
references.pmid: 20618770
references.citation: J Immunol. 2006 Jul 1;177(1):77-83
references.pmid: 16785501
references.citation: Mol Immunol. 2005 Feb;42(4):463-9
references.pmid: 15607800
references.citation: J Exp Med. 1995 Mar 1;181(3):1235-8
references.pmid: 7532682