In Cystic Fibrosis Homozygotes and Heterozygotes, Neutrophil Apoptosis Is Delayed and Modulated by Diamide or Roscovitine: Evidence for an Innate Neutrophil DisturbanceMoriceau S.a · Lenoir G.b · Witko-Sarsat V.a, c
aINSERM U845 and bDepartment of General Pediatrics, Necker Hospital, cINSERM U1016-CNRS UMR 8104-Université Paris Descartes, Cochin Hospital, Paris, France
Dr. Véronique Witko-Sarsat
INSERM U1016, Cochin Institute, Immunology-Hematology Department
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FR–75014 Paris (France)
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Cystic fibrosis (CF) is a chronic inflammatory lung disease characterized by polymorphonuclear neutrophil (PMN)-dominated airway inflammation. Defective apoptosis might explain PMN persistence at these inflammation sites. We previously reported that in CF patients PMN underwent delayed apoptosis, which was not always related to their infectious state and independent of the type of CF transmembrane regulator (CFTR) mutation. To understand the role of infection and PMN apoptosis in CF, PMN apoptosis was investigated in CF parents who are obligate heterozygotes for the CFTR mutation but without chronic bacterial infection. They also demonstrated delayed PMN apoptosis compared with healthy controls, as assessed by annexin-V labeling and caspase-3 cleavage. Diamide, a direct thiol-oxidizing agent, potentiated PMN apoptosis in controls and CF patients, resulting in similar levels of constitutive and Fas-potentiated apoptosis. The cyclin-dependent kinase inhibitor roscovitine provided another approach to restore normal PMN apoptosis. However, the selective CFTR inhibitor CFTRInh172 did not affect PMN apoptosis in control subjects. Apparently, the dysregulation of CF PMN is not only a consequence of the chronic infectious state in CF children but might also be related to CF ‘intrinsic’ factors. Restoration of normal PMN apoptosis by cellular redox modulation or roscovitine opens new research avenues to decrease PMN-mediated inflammation in CF.
© 2010 S. Karger AG, Basel
- Cantin A: Cystic fibrosis lung inflammation: early, sustained, and severe. Am J Respir Crit Care Med 1995;151:939–941.
- Nichols D, Chmiel J, Berger M: Chronic inflammation in the cystic fibrosis lung: alterations in inter- and intracellular signaling. Clin Rev Allergy Immunol 2008;34:146–162.
- Witko-Sarsat V, Halbwachs-Mecarelli L, Schuster A, Nusbaum P, Ueki I, Canteloup S, Lenoir G, Descamps-Latscha B, Nadel JA: Proteinase 3, a potent secretagogue in airways, is present in cystic fibrosis sputum. Am J Respir Cell Mol Biol 1999;20:729–736.
- Bals R, Weiner DJ, Wilson JM: The innate immune system in cystic fibrosis lung disease. J Clin Invest 1999;103:303–307.
- Doring G, Gulbins E: Cystic fibrosis and innate immunity: how chloride channel mutations provoke lung disease. Cell Microbiol 2009;11:208–216.
- Downey DG, Bell SC, Elborn JS: Neutrophils in cystic fibrosis. Thorax 2009;64:81–88.
- Russell KJ, McRedmond J, Mukherji N, Costello C, Keatings V, Linnane S, Henry M, Fitzgerald MX, O’Connor CM: Neutrophil adhesion molecule surface expression and responsiveness in cystic fibrosis. Am J Respir Crit Care Med 1998;157:756–761.
- Witko-Sarsat V, Halbwachs-Mecarelli L, Sermet-Gaudelus I, Bessou G, Lenoir G, Allen RC, Descamps-Latscha B: Priming of blood neutrophils in children with cystic fibrosis: correlation between functional and phenotypic expression of opsonin receptors before and after platelet-activating factor priming. J Infect Dis 1999;179:151–162.
- Adib-Conquy M, Pedron T, Petit-Bertron AF, Tabary O, Corvol H, Jacquot J, Clement A, Cavaillon JM: Neutrophils in cystic fibrosis display a distinct gene expression pattern. Mol Med 2008;14:36–44.
- Witko-Sarsat V, Allen RC, Paulais M, Nguyen AT, Bessou G, Lenoir G, Descamps-Latscha B: Disturbed myeloperoxidase-dependent activity of neutrophils in cystic fibrosis homozygotes and heterozygotes, and its correction by amiloride. J Immunol 1996;157:2728–2735.
- Sermet-Gaudelus I, Dechaux M, Vallee B, Fajac A, Girodon E, Nguyen-Khoa T, Marianovski R, Hurbain I, Bresson JL, Lenoir G, Edelman A: Chloride transport in nasal ciliated cells of cystic fibrosis heterozygotes. Am J Respir Crit Care Med 2005;171:1026–1031.
- Rossi AG, Hallett JM, Sawatzky DA, Teixeira MM, Haslett C: Modulation of granulocyte apoptosis can influence the resolution of inflammation. Biochem Soc Trans 2007;35:288–291.
- Hallett JM, Leitch AE, Riley NA, Duffin R, Haslett C, Rossi AG: Novel pharmacological strategies for driving inflammatory cell apoptosis and enhancing the resolution of inflammation. Trends Pharmacol Sci 2008;29:250–257.
- Moriceau S, Kantari C, Mocek J, Davezac N, Gabillet J, Guerrera IC, Brouillard F, Tondelier D, Sermet-Gaudelus I, Danel C, Lenoir G, Daniel S, Edelman A, Witko-Sarsat V: Coronin-1 is associated with neutrophil survival and is cleaved during apoptosis: potential implication in neutrophils from cystic fibrosis patients. J Immunol 2009;182:7254–7263.
- McKeon DJ, Condliffe AM, Cowburn AS, Cadwallader KC, Farahi N, Bilton D, Chilvers ER: Prolonged survival of neutrophils from patients with delta F508 CFTR mutations. Thorax 2008;63:660–661.
- Dibbert B, Weber M, Nikolaizik WH, Vogt P, Schoni MH, Blaser K, Simon HU: Cytokine-mediated Bax deficiency and consequent delayed neutrophil apoptosis: a general mechanism to accumulate effector cells in inflammation. Proc Natl Acad Sci USA 1999;96:13330–13335.
- Kantari C, Pederzoli-Ribeil M, Amir-Moazami O, Gausson-Dorey V, Moura IC, Lecomte MC, Benhamou M, Witko-Sarsat V: Proteinase 3, the Wegener autoantigen, is externalized during neutrophil apoptosis: evidence for a functional association with phospholipid scramblase 1 and interference with macrophage phagocytosis. Blood 2007;110:4086–4095.
- Pardo J, Urban C, Galvez EM, Ekert PG, Muller U, Kwon-Chung J, Lobigs M, Mullbacher A, Wallich R, Borner C, Simon MM: The mitochondrial protein Bak is pivotal for gliotoxin-induced apoptosis and a critical host factor of Aspergillus fumigatus virulence in mice. J Cell Biol 2006;174:509–519.
- Ward C, Chilvers ER, Lawson MF, Pryde JG, Fujihara S, Farrow SN, Haslett C, Rossi AG: NF-ĸB activation is a critical regulator of human granulocyte apoptosis in vitro. J Biol Chem 1999;274:4309–4318.
- Scheel-Toellner D, Wang K, Craddock R, Webb PR, McGettrick HM, Assi LK, Parkes N, Clough LE, Gulbins E, Salmon M, Lord JM: Reactive oxygen species limit neutrophil life span by activating death receptor signaling. Blood 2004;104:2557–2564.
- O’Neill AJ, O’Neill S, Hegarty NJ, Coffey RN, Gibbons N, Brady H, Fitzpatrick JM, Watson RW: Glutathione depletion-induced neutrophil apoptosis is caspase 3 dependent. Shock 2000;14:605–609.
- Rossi AG, Sawatzky DA, Walker A, Ward C, Sheldrake TA, Riley NA, Caldicott A, Martinez-Losa M, Walker TR, Duffin R, Gray M, Crescenzi E, Martin MC, Brady HJ, Savill JS, Dransfield I, Haslett C: Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis. Nat Med 2006;12:1056–1064.
- Koedel U, Frankenberg T, Kirschnek S, Obermaier B, Häcker H, Paul R, Häcker G: Apoptosis is essential for neutrophil functional shutdown and determines tissue damage in experimental pneumococcal meningitis. PLoS Pathog 2009;5:e1000461.
- Painter RG, Valentine VG, Lanson NA Jr, Leidal K, Zhang Q, Lombard G, Thompson C, Viswanathan A, Nauseef WM, Wang G, Wang G: CFTR expression in human neutrophils and the phagolysosomal chlorination defect in cystic fibrosis. Biochemistry 2006;45:10260–10269.
- Ma T, Thiagarajah JR, Yang H, Sonawane ND, Folli C, Galietta LJ, Verkman AS: Thiazolidinone CFTR inhibitor identified by high-throughput screening blocks cholera toxin-induced intestinal fluid secretion. J Clin Invest 2002;110:1651–1658.
- Gottlieb RA, Dosanjh A: Mutant cystic fibrosis transmembrane conductance regulator inhibits acidification and apoptosis in C127 cells: possible relevance to cystic fibrosis. Proc Natl Acad Sci USA 1996;93:3587–3591.
- Jungas T, Motta I, Duffieux F, Fanen P, Stoven V, Ojcius DM: Glutathione levels and Bax activation during apoptosis due to oxidative stress in cells expressing wild-type and mutant cystic fibrosis transmembrane conductance regulator. J Biol Chem 2002;277:27912–27918.
- Hudson VM: Rethinking cystic fibrosis pathology: the critical role of abnormal reduced glutathione (GSH) transport caused by CFTR mutation. Free Radic Biol Med 2001;30:1440–1461.
- Linsdell P, Hanrahan JW: Glutathione permeability of CFTR. Am J Physiol 1998;275:C323–C326.
- Watson RW: Redox regulation of neutrophil apoptosis. Antioxid Redox Signal 2002;4:97–104.
- Fadeel B, Ahlin A, Henter JI, Orrenius S, Hampton MB: Involvement of caspases in neutrophil apoptosis: regulation by reactive oxygen species. Blood 1998;92:4808–4818.
- Konstan MW, Byard PJ, Hoppel CL, Davis PB: Effect of high-dose ibuprofen in patients with cystic fibrosis. N Engl J Med 1995;332:848–854.
- Balfour-Lynn IM, Lees B, Hall P, Phillips G, Khan M, Flather M, Elborn JS: Multicenter randomized controlled trial of withdrawal of inhaled corticosteroids in cystic fibrosis. Am J Respir Crit Care Med 2006;173:1356–1362.
- Gu Y, Harley IT, Henderson LB, Aronow BJ, Vietor I, Huber LA, Harley JB, Kilpatrick JR, Langefeld CD, Williams AH, Jegga AG, Chen J, Wills-Karp M, Arshad SH, Ewart SL, Thio CL, Flick LM, Filippi MD, Grimes HL, Drumm ML, Cutting GR, Knowles MR, Karp CL: Identification of IFRD1 as a modifier gene for cystic fibrosis lung disease. Nature 2009;458:1039–1042.
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