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.
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
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
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
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
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
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
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
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
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
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.
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
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
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
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
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
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
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
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.
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
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
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
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
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
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
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
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
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
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
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
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
