All Title Author
Keywords Abstract

PLOS ONE  2014 

Oxidative Stress Decreases Functional Airway Mannose Binding Lectin in COPD

DOI: 10.1371/journal.pone.0098571

Full-Text   Cite this paper   Add to My Lib


We have previously established that a defect in the ability of alveolar macrophages (AM) to phagocytose apoptotic cells (efferocytosis) and pathogens is a potential therapeutic target in COPD. We further showed that levels of mannose binding lectin (MBL; required for effective macrophage phagocytic function) were reduced in the airways but not circulation of COPD patients. We hypothesized that increased oxidative stress in the airway could be a cause for such disturbances. We therefore studied the effects of oxidation on the structure of the MBL molecule and its functional interactions with macrophages. Oligomeric structure of plasma derived MBL (pdMBL) before and after oxidation (oxMBL) with 2,2′-azobis(2-methylpropionamidine)dihyd?rochroride(AAPH) was investigated by blue native PAGE. Macrophage function in the presence of pd/oxMBL was assessed by measuring efferocytosis, phagocytosis of non-typeable Haemophilus influenzae (NTHi) and expression of macrophage scavenger receptors. Oxidation disrupted higher order MBL oligomers. This was associated with changed macrophage function evident by a significantly reduced capacity to phagocytose apoptotic cells and NTHi in the presence of oxMBL vs pdMBL (eg, NTHi by 55.9 and 27.0% respectively). Interestingly, oxidation of MBL significantly reduced macrophage phagocytic ability to below control levels. Flow cytometry and immunofluorescence revealed a significant increase in expression of macrophage scavenger receptor (SRA1) in the presence of pdMBL that was abrogated in the presence of oxMBL. We show the pulmonary macrophage dysfunction in COPD may at least partially result from an oxidative stress-induced effect on MBL, and identify a further potential therapeutic strategy for this debilitating disease.


[1]  World Health Statistics (2008) Theakston F, ed. Geneva: World Health Organization; 2008.
[2]  Hodge S, Hodge G, Scicchitano R, Reynolds PN, Holmes M (2003) Alveolar macrophages from subjects with chronic obstructive pulmonary disease are deficient in their ability to phagocytose apoptotic airway epithelial cells. Immunol Cell Biol 81: 289–96. doi: 10.1046/j.1440-1711.2003.t01-1-01170.x
[3]  Hodge S, Hodge G, Ahern J, Jersmann H, Holmes M, et al. (2007) Smoking alters alveolar macrophage recognition and phagocytic ability: implications in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 37: 748–55. doi: 10.1165/rcmb.2007-0025oc
[4]  Dehle FC, Mukaro VR, Jurisevic C, Moffat D, Ahern J, et al. (2013) Defective lung macrophage function in lung cancer ± chronic obstructive pulmonary disease (COPD/emphysema)-mediated by cancer cell production of PGE2? PLoS One 8(4): e61573. doi: 10.1371/journal.pone.0061573
[5]  Hodge S, Hodge G, Holmes M, Reynolds PN (2005) Increased airway epithelial and T-cell apoptosis in COPD remains despite smoking cessation. Eur Respir J 25: 447–54. doi: 10.1183/09031936.05.00077604
[6]  Hodge S, Reynolds PN (2012) Low-dose azithromycin improves phagocytosis of bacteria by both alveolar and monocyte-derived macrophages in chronic obstructive pulmonary disease subjects. Respirology 17(5): 802–7. doi: 10.1111/j.1440-1843.2012.02135.x
[7]  Wilkinson TM, Patel IS, Wilks M, Donaldson GC, Wedzicha JA (2003) Airway bacterial load and FEV1 decline in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 167: 1090–5. doi: 10.1164/rccm.200210-1179oc
[8]  Hodge S, Dean M, Hodge G, Holmes M, Reynolds PN (2011) Decreased efferocytosis and mannose binding lectin in the airway in bronchiolitis obliterans syndrome. J Heart Lung Transplant 30(5): 589–95. doi: 10.1016/j.healun.2011.01.710
[9]  Simpson JL, Gibson PG, Yang IA, Upham J, James A, et al. (2013) Impaired macrophage phagocytosis in non-eosinophilic asthma. Clin Exp Allergy 43(1): 29–35. doi: 10.1111/j.1365-2222.2012.04075.x
[10]  Hodge S, Hodge G, Brozyna S, Jersmann H, Holmes M, et al. (2006) Azithromycin increases phagocytosis of apoptotic bronchial epithelial cells by alveolar macrophages. Eur Respir J 28(3): 486–95. doi: 10.1183/09031936.06.00001506
[11]  Hodge S, Hodge G, Jersmann H, Matthews G, Ahern J, et al. (2008) Azithromycin improves macrophage phagocytic function and expression of mannose receptor in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 178(2): 139–48. doi: 10.1164/rccm.200711-1666oc
[12]  Hodge S, Matthews G, Dean MM, Ahern J, Djukic M, et al. (2010) Therapeutic role for mannose-binding lectin in cigarette smoke-induced lung inflammation? Evidence from a murine model. Am J Respir Cell Mol Biol 42(2): 235–42. doi: 10.1165/rcmb.2008-0486oc
[13]  Hodge S, Matthews G, Mukaro V, Ahern J, Shivam A, et al. (2011) Cigarette smoke-induced changes to alveolar macrophage phenotype and function are improved by treatment with procysteine. Am J Respir Cell Mol Biol 44(5): 673–81. doi: 10.1165/rcmb.2009-0459oc
[14]  Mukaro VR, Bylund J, Hodge G, Holmes M, Jersmann H, et al. (2013) Lectins offer new perspectives in the development of macrophage-targeted therapies for COPD/emphysema. PLoS One 8(2): e56147. doi: 10.1371/journal.pone.0056147
[15]  Nakanishi Y, Kobayashi D, Asano Y, Sakurai T, Kashimura M, et al. (2009) Clarithromycin prevents smoke-induced emphysema in mice. Am J Respir Crit Care Med 179(4): 271–8. doi: 10.1164/rccm.200806-905oc
[16]  Ogden CA, deCathelineau A, Hoffmann PR, Bratton D, Ghebrehiwet B, et al. (2001) C1q and mannose binding lectin engagement of cell surface calreticulin and CD91 initiates macropinocytosis and uptake of apoptotic cells. J Exp Med 194(6): 781–95. doi: 10.1084/jem.194.6.781
[17]  Nauta AJ, Raaschou-Jensen N, Roos A, Daha MR, Madsen HO, et al. (2003) Eur J Immunol. 33(10): 2853–63. Mannose-binding lectin engagement with late apoptotic and necrotic cells.
[18]  Fidler KJ, Hilliard TN, Bush A, Johnson M, Geddes DM (2009) Mannose-binding lectin is present in the infected airway: a possible pulmonary defence mechanism. Thorax 64(2): 150–5. doi: 10.1136/thx.2008.100073
[19]  Teillet F, Dublet B, Andrieu JP, Gaboriaud C, Arlaud GJ, et al. (2005) The two major oligomeric forms of human mannan-binding lectin: chemical characterization, carbohydrate-binding properties, and interaction with MBL-associated serine proteases. J Immunol 174(5): 2870–7. doi: 10.4049/jimmunol.174.5.2870
[20]  Butler GS, Sim D, Tam E, Devine D, Overall CM (2002) Mannose-binding lectin (MBL) mutants are susceptible to matrix metalloproteinase proteolysis: potential role in human MBL deficiency. J Biol Chem 277(20): 17511–9. doi: 10.1074/jbc.m201461200
[21]  Kirkham PA, Barnes PJ (2013) Oxidative stress in COPD. Chest 144(1): 266–73. doi: 10.1378/chest.12-2664
[22]  Wittig I, Beckhaus T, Wumaier Z, Karas M, Sch?gger H (2010) Mass estimation of native proteins by blue native electrophoresis: principles and practical hints. Mol Cell Proteomics 9(10) 2149–61: 20. doi: 10.1074/mcp.m900526-mcp200
[23]  Ono K, Nishitani C, Mitsuzawa H, Shimizu T, Sano H, et al. (2006) Mannose-binding lectin augments the uptake of lipid A, Staphylococcus aureus, and Escherichia coli by Kupffer cells through increased cell surface expression of scavenger receptor A. J Immunol. 177(8): 5517–23. doi: 10.4049/jimmunol.177.8.5517
[24]  Hoenderdos K, Condliffe A (2013) The neutrophil in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 48(5): 531–9. doi: 10.1165/rcmb.2012-0492tr
[25]  Kuzmenko AI, Wu H, Wan S, McMormack FX (2005) Surfactant protein A is a principal and oxidation-sensitive microbial permeabilising factor in the alveolar lining fluid. J Biol Chem 280(27): 25913–9. doi: 10.1074/jbc.m411344200
[26]  Starosta V, Griese M (2006) Protein oxidation by chronic pulmonary diseases in children. Pediatr Pulmonol 41(1): 67–73. doi: 10.1002/ppul.20289
[27]  Starosta V, Griese M (2006) Oxidative damage to surfactant protein D in pulmonary diseases. Free Radic Res 40(4): 419–25. doi: 10.1080/10715760600571248
[28]  Lipscombe RJ, Sumiya M, Summerfield JA, Turner MW (1995) Distinct physicochemical characteristics of human mannose binding protein expressed by individuals of differing genotype. Immunology 85(4): 660–7.
[29]  Terai I, Kobayashi K, Matsushita M, Miyakawa H, Mafune N, et al. (2003) Relationship between gene polymorphisms of mannose-binding lectin (MBL) and two molecular forms of MBL. Eur J Immunol 33(10): 2755–63. doi: 10.1002/eji.200323955
[30]  Ghiran I, Barbashov SF, Klickstein LB, Tas SW, Jensenius JC, et al. (2000) Complement receptor 1/CD35 is a receptor for mannan-binding lectin. J Exp Med. 192(12): 1797–808. doi: 10.1084/jem.192.12.1797
[31]  Moghaddam SJ, Ochoa CE, Sethi S, Dickey BF (2011) Nontypeable Haemophilus influenzae in chronic obstructive pulmonary disease and lung cancer. Int J Chron Obstruct Pulmon Dis 6: 113–123.
[32]  Krarup A, Sorensen UB, Matsushita M, Jensenius JC, Thiel S (2005) Effect of capsulation of opportunistic pathogenic bacteria on binding of the pattern recognition molecules mannan-binding lectin, L-ficolin, and H-ficolin. Infect Immun 73(2): 1052–60. doi: 10.1128/iai.73.2.1052-1060.2005
[33]  Platt N, Suzuki H, Kurihara Y, Kodama T, Gordon S (1996) Role for the class A macrophage scavenger receptor in the phagocytosis of apoptotic thymocytes in vitro. Proc Natl Acad Sci USA 93(22): 12456–60. doi: 10.1073/pnas.93.22.12456
[34]  Peiser L, De Winther MP, Makepeace K, Hollinshead M, Coull P, et al. (2012) The class A macrophage scavenger receptor is a major pattern recognition receptor for Neisseria menigitidis which is independent of liposaccharide and not required for secretory responses, Infect Immun. 70(10): 5346–54. doi: 10.1128/iai.70.10.5346-5354.2002
[35]  Todt JC, Hu B, Curtis JL (2008) The scavenger receptor SR-A I/II signals via the receptor tyrosine kinase Merttk during apoptotic cell uptake by murine macrophages, J Leukoc Biol 84(2) 510–8.
[36]  Kuronuma K, Sano H, Kato K, Kudo K, Hyakushima N, et al. (2004) Pulmonary surfactant protein A augments the phagocytosis of Streptococcus pneumoniae by alveolar macrophages through a casein kinase 2-dependent increase of cell surface localization of scavenger receptor A. J Biol Chem. 279(20): 21421–30. doi: 10.1074/jbc.m312490200
[37]  Fraser DA, Bohlson SS, Jasinskiene N, Rawal N, Palmarini G, et al. (2006) C1q and MBL, components of the innate immune system, influence monocyte cytokine expression. J Leucok Biol 80(1): 107–16. doi: 10.1189/jlb.1105683
[38]  Shimizu T, Nishitani C, Mitsuzawa H, Ariki S, Takahashi M, et al. (2009) Mannose binding lectin and lung collectins interact with Toll-like receptor 4 and MD-2 by different mechanisms. Biochim Biophys Acta 1790(12): 1705–10. doi: 10.1016/j.bbagen.2009.10.006
[39]  Wang M, Chen Y, Zhang Y, Zhang L, Lu X, et al. (2011) Mannan-binding lectin directly interacts with Toll-like receptor 4 and suppresses lipopolysaccharide-induced inflammatory cytokine secretion from THP-1 cells. Cell Mol Immunol 8: 265–275. doi: 10.1038/cmi.2011.1
[40]  Wang M, Wang F, Yang J, Zhao D, Wang H, et al. (2013) Mannan-Binding Lectin Inhibits Candida albicans-Induced Cellular Responses in PMA-Activated THP-1 Cells through Toll-Like Receptor 2 and Toll-Like Receptor 4. PLoS One 8(12): e83517. doi: 10.1371/journal.pone.0083517
[41]  Yu X, Yi H, Guo C, Zuo D, Wang Y, et al. (2011) Pattern recognition scavenger receptor CD204 attenuates Toll-like receptor 4-induced NF-kappaB activation by directly inhibiting ubiquitination of tumor necrosis factor (TNF) receptor-associated factor 6. J Biol Chem 286(21): 18795–806. doi: 10.1074/jbc.m111.224345
[42]  Ozment TR, Ha T, Breuel KF, Ford TR, Ferguson DA, et al. (2012) Scavenger receptor class a plays a central role in mediating mortality and the development of the pro-inflammatory phenotype in polymicrobial sepsis. PLoS Pathog 8(10): e1002967. doi: 10.1371/journal.ppat.1002967
[43]  Bang P, Laursen I, Thornberg K, Schierbeck J, Nielsen B, et al. (2008) The pharmacokinetic profile of plasma-derived mannan-binding lectin in healthy adult volunteers and patients with Staphylococcus aureus septicaemia. Scand J Infect Dis 40(1): 44–8. doi: 10.1080/00365540701522959
[44]  Valdimarsson H (2003) Infusion of plasma-derived mannan-binding lectin (MBL) into MBL-deficient humans. Biochem Soc Trans 31(Pt 4): 768–9. doi: 10.1042/bst0310768


comments powered by Disqus

Contact Us


微信:OALib Journal