The Korean journal of internal medicine

The Korean Association of Internal Medicine (대한내과학회)
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Association of autophagy related gene polymorphisms with neutrophilic airway inflammation in adult asthma

  • Pham, Duy Le (Department of Biomedical Sciences, Ajou University School of Medicine) ;
  • Kim, Seung-Hyun (Department of Allergy and Clinical Immunology, Ajou University School of Medicine) ;
  • Losol, Purevsuren (Department of Molecular Biology and Genetics, Health Sciences University of Mongolia) ;
  • Yang, Eun-Mi (Department of Allergy and Clinical Immunology, Ajou University School of Medicine) ;
  • Shin, Yoo Seob (Department of Allergy and Clinical Immunology, Ajou University School of Medicine) ;
  • Ye, Young-Min (Department of Allergy and Clinical Immunology, Ajou University School of Medicine) ;
  • Park, Hae-Sim (Department of Biomedical Sciences, Ajou University School of Medicine)
  • Received : 2014.12.26
  • Accepted : 2015.08.17
  • Published : 2016.03.01
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Abstract

Background/Aims: Role of autophagy in neutrophil function and the association of autophagy and autophagy related (ATG) gene polymorphisms with asthma susceptibility were suggested. In this study, we investigated the genetic association of ATG5 and ATG7 polymorphisms with asthma risk, severity and neutrophilic airway inflammation. Methods: We recruited 408 asthma patients and 201 healthy controls. Sputum neutrophil counts were determined by H&E staining. Serum interleukin 8 (IL-8) levels were measured by enzyme-linked immunosorbent assay (ELISA). Genetic polymorphisms of ATG5 (-769T>C, -335G>A, and 8830C>T) and ATG7 (-100A>G and 25108G>C) were genotyped. The functional activities of ATG5 -769T>C and -335G>A variants were investigated by luciferase reporter assays. Results: No associations of ATG5 and ATG7 polymorphisms with asthma susceptibility and severity were found. ATG5 -769T>C and -335G>A were in complete linkage disequilibrium. In the asthma group, GA/AA genotypes at ATG5 -335G>A were associated with higher neutrophil counts in sputum (p < 0.05); CC/TT genotype at ATG5 8830C>T associated with lower FEV1% predicted value (p < 0.05). DNA fragments containing ATG5 -769T and -335G alleles had higher promoter activities compared to those with -769C and -335A in both human airway epithelial cells (A549, p < 0.01) and human mast cell (HMC-1, p < 0.001). GG and CC genotype at ATG7 -100A>G and 25108G>C were significantly associated with high serum levels of IL-8 (p < 0.05 for both variants). Conclusions: Genetic polymorphisms of ATG5 and ATG7 could contribute to neutrophilic airway inflammation in the pathogenesis of adult asthma.

Keywords

Acknowledgement

Supported by : Ministry of Health and Welfare

References

  1. Lotvall J, Akdis CA, Bacharier LB, et al. Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol 2011;127:355-360. https://doi.org/10.1016/j.jaci.2010.11.037
  2. Holgate ST. Mechanisms of asthma and implications for its prevention and treatment: a personal journey. Allergy Asthma Immunol Res 2013;5:343-347. https://doi.org/10.4168/aair.2013.5.6.343
  3. Fahy JV. Eosinophilic and neutrophilic inflammation in asthma: insights from clinical studies. Proc Am Thorac Soc 2009;6:256-259. https://doi.org/10.1513/pats.200808-087RM
  4. Jo EJ, Kim MY, Lee SE, et al. Eosinophilic airway inflammation and airway hyperresponsiveness according to aeroallergen sensitization pattern in patients with lower airway symptoms. Allergy Asthma Immunol Res 2014;6:39-46. https://doi.org/10.4168/aair.2014.6.1.39
  5. Schleich FN, Manise M, Sele J, Henket M, Seidel L, Louis R. Distribution of sputum cellular phenotype in a large asthma cohort: predicting factors for eosinophilic vs neutrophilic inflammation. BMC Pulm Med 2013;13:11. https://doi.org/10.1186/1471-2466-13-11
  6. Douwes J, Gibson P, Pekkanen J, Pearce N. Non-eosinophilic asthma: importance and possible mechanisms. Thorax 2002;57:643-648. https://doi.org/10.1136/thorax.57.7.643
  7. Deretic V, Saitoh T, Akira S. Autophagy in infection, inflammation and immunity. Nat Rev Immunol 2013;13:722-737. https://doi.org/10.1038/nri3532
  8. Ryter SW, Choi AM. Autophagy in the lung. Proc Am Thorac Soc 2010;7:13-21. https://doi.org/10.1513/pats.200909-101JS
  9. Bhattacharya A, Eissa NT. Autophagy and autoimmunity crosstalks. Front Immunol 2013;4:88.
  10. Mihalache CC, Simon HU. Autophagy regulation in macrophages and neutrophils. Exp Cell Res 2012;318:1187-1192. https://doi.org/10.1016/j.yexcr.2011.12.021
  11. Ushio H, Ueno T, Kojima Y, et al. Crucial role for autophagy in degranulation of mast cells. J Allergy Clin Immunol 2011;127:1267-1276.e6. https://doi.org/10.1016/j.jaci.2010.12.1078
  12. Remijsen Q, Vanden Berghe T, Wirawan E, et al. Neutrophil extracellular trap cell death requires both autophagy and superoxide generation. Cell Res 2011;21:290-304. https://doi.org/10.1038/cr.2010.150
  13. Poon AH, Chouiali F, Tse SM, et al. Genetic and histologic evidence for autophagy in asthma pathogenesis. J Allergy Clin Immunol 2012;129:569-571. https://doi.org/10.1016/j.jaci.2011.09.035
  14. Martin LJ, Gupta J, Jyothula SS, et al. Functional variant in the autophagy-related 5 gene promotor is associated with childhood asthma. PLoS One 2012;7:e33454. https://doi.org/10.1371/journal.pone.0033454
  15. Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 2014;43:343-373. https://doi.org/10.1183/09031936.00202013
  16. Park HS, Kim HY, Nahm DH, Son JW, Kim YY. Specific IgG, but not specific IgE, antibodies to toluene diisocyanate-human serum albumin conjugate are associated with toluene diisocyanate bronchoprovocation test results. J Allergy Clin Immunol 1999;104(4 Pt 1):847-851. https://doi.org/10.1016/S0091-6749(99)70297-6
  17. Nahm DH, Park HS. Analysis of induced sputum for studying allergen-specific IgE antibodies in airway secretion from asthmatic patients. Clin Exp Allergy 1998;28:686-693. https://doi.org/10.1046/j.1365-2222.1998.00291.x
  18. Lunetta KL. Genetic association studies. Circulation 2008;118:96-101. https://doi.org/10.1161/CIRCULATIONAHA.107.700401
  19. Yousefi S, Perozzo R, Schmid I, et al. Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis. Nat Cell Biol 2006;8:1124-1132. https://doi.org/10.1038/ncb1482
  20. Pyo JO, Jang MH, Kwon YK, et al. Essential roles of Atg5 and FADD in autophagic cell death: dissection of autophagic cell death into vacuole formation and cell death. J Biol Chem 2005;280:20722-20729. https://doi.org/10.1074/jbc.M413934200
  21. Hosokawa N, Hara Y, Mizushima N. Generation of cell lines with tetracycline-regulated autophagy and a role for autophagy in controlling cell size. FEBS Lett 2006;580:2623-2629. https://doi.org/10.1016/j.febslet.2006.04.008
  22. Huang J, Canadien V, Lam GY, et al. Activation of antibacterial autophagy by NADPH oxidases. Proc Natl Acad Sci U S A 2009;106:6226-6231. https://doi.org/10.1073/pnas.0811045106
  23. Mitroulis I, Kourtzelis I, Kambas K, et al. Regulation of the autophagic machinery in human neutrophils. Eur J Immunol 2010;40:1461-1472. https://doi.org/10.1002/eji.200940025
  24. Scherz-Shouval R, Elazar Z. Regulation of autophagy by ROS: physiology and pathology. Trends Biochem Sci 2011;36:30-38. https://doi.org/10.1016/j.tibs.2010.07.007
  25. Dworski R. Oxidant stress in asthma. Thorax 2000;55 Suppl 2:S51-S53.
  26. He MX, McLeod IX, Jia W, He YW. Macroautophagy in T lymphocyte development and function. Front Immunol 2012;3:22.
  27. Pua HH, Dzhagalov I, Chuck M, Mizushima N, He YW. A critical role for the autophagy gene Atg5 in T cell survival and proliferation. J Exp Med 2007;204:25-31. https://doi.org/10.1084/jem.20061303
  28. Conway KL, Kuballa P, Khor B, et al. ATG5 regulates plasma cell differentiation. Autophagy 2013;9:528-537. https://doi.org/10.4161/auto.23484
  29. Jyothula SS, Eissa NT. Autophagy and role in asthma. Curr Opin Pulm Med 2013;19:30-35. https://doi.org/10.1097/MCP.0b013e32835b1150
  30. Dworski R, Simon HU, Hoskins A, Yousefi S. Eosinophil and neutrophil extracellular DNA traps in human allergic asthmatic airways. J Allergy Clin Immunol 2011;127:1260-1266. https://doi.org/10.1016/j.jaci.2010.12.1103
  31. Brinkmann V, Reichard U, Goosmann C, et al. Neutrophil extracellular traps kill bacteria. Science 2004;303:1532-1535. https://doi.org/10.1126/science.1092385
  32. Cheng OZ, Palaniyar N. NET balancing: a problem in inflammatory lung diseases. Front Immunol 2013;4:1.
  33. Jatakanon A, Uasuf C, Maziak W, Lim S, Chung KF, Barnes PJ. Neutrophilic inflammation in severe persistent asthma. Am J Respir Crit Care Med 1999;160(5 Pt 1):1532-1539. https://doi.org/10.1164/ajrccm.160.5.9806170
  34. Kikuchi S, Nagata M, Kikuchi I, Hagiwara K, Kanazawa M. Association between neutrophilic and eosinophilic inflammation in patients with severe persistent asthma. Int Arch Allergy Immunol 2005;137 Suppl 1:7-11. https://doi.org/10.1159/000085425
  35. Silvestri M, Bontempelli M, Giacomelli M, et al. High serum levels of tumour necrosis factor-alpha and interleukin-8 in severe asthma: markers of systemic inflammation? Clin Exp Allergy 2006;36:1373-1381. https://doi.org/10.1111/j.1365-2222.2006.02502.x
  36. Chun YH, Park JY, Lee H, et al. Rhinovirus-infected epithelial cells produce more IL-8 and RANTES compared with other respiratory viruses. Allergy Asthma Immunol Res 2013;5:216-223. https://doi.org/10.4168/aair.2013.5.4.216

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