Tuberc Respir Dis.  2016 Jan;79(1):5-13. 10.4046/trd.2016.79.1.5.

The Role of Innate and Adaptive Immune Cells in the Immunopathogenesis of Chronic Obstructive Pulmonary Disease

• Nurwidya F
• Damayanti
• Yunus F

• KMID: 2320750
• DOI: http://doi.org/10.4046/trd.2016.79.1.5

Abstract

Chronic obstructive pulmonary disease (COPD) is a chronic and progressive inflammatory disease of the airways and lungs that results in limitations of continuous airflow and is caused by exposure to noxious gasses and particles. A major cause of morbidity and mortality in adults, COPD is a complex disease pathologically mediated by many inflammatory pathways. Macrophages, neutrophils, dendritic cells, and CD8+ T-lymphocytes are the key inflammatory cells involved in COPD. Recently, the non-coding small RNA, micro-RNA, have also been intensively investigated and evidence suggest that it plays a role in the pathogenesis of COPD. Here, we discuss the accumulated evidence that has since revealed the role of each inflammatory cell and their involvement in the immunopathogenesis of COPD. Mechanisms of steroid resistance in COPD will also be briefly discussed.

Keyword

Pulmonary Disease, Chronic Obstructive; Macrophages; Neutrophils; Dendritic Cells; Lymphocytes

MeSH Terms

Adult
Dendritic Cells
Humans
Lung
Lymphocytes
Macrophages
Mortality
Neutrophils
Pulmonary Disease, Chronic Obstructive*
RNA
T-Lymphocytes
RNA

Reference

1. Raherison C, Girodet PO. Epidemiology of COPD. Eur Respir Rev. 2009; 18:213–221.

2. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012; 380:2095–2128.

3. Afonso AS, Verhamme KM, Sturkenboom MC, Brusselle GG. COPD in the general population: prevalence, incidence and survival. Respir Med. 2011; 105:1872–1884.

4. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Global Initiative for Chronic Obstructive Lung Disease;2014.

5. Bellinger CR, Peters SP. Outpatient chronic obstructive pulmonary disease management: going for the GOLD. J Allergy Clin Immunol Pract. 2015; 3:471–478.

6. Salvi S. Tobacco smoking and environmental risk factors for chronic obstructive pulmonary disease. Clin Chest Med. 2014; 35:17–27.

7. Eisner MD, Anthonisen N, Coultas D, Kuenzli N, Perez-Padilla R, Postma D, et al. An official American Thoracic Society public policy statement: novel risk factors and the global burden of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2010; 182:693–718.

8. Mehta H, Nazzal K, Sadikot RT. Cigarette smoking and innate immunity. Inflamm Res. 2008; 57:497–503.

9. Lugade AA, Bogner PN, Thatcher TH, Sime PJ, Phipps RP, Thanavala Y. Cigarette smoke exposure exacerbates lung inflammation and compromises immunity to bacterial infection. J Immunol. 2014; 192:5226–5235.

10. Rinaldi M, Maes K, De Vleeschauwer S, Thomas D, Verbeken EK, Decramer M, et al. Long-term nose-only cigarette smoke exposure induces emphysema and mild skeletal muscle dysfunction in mice. Dis Model Mech. 2012; 5:333–341.

11. Tsuji H, Fujimoto H, Lee KM, Renne R, Iwanaga A, Okubo C, et al. Characterization of biochemical, functional and structural changes in mice respiratory organs chronically exposed to cigarette smoke. Inhal Toxicol. 2015; 27:342–353.

12. Wang G, Wang R, Strulovici-Barel Y, Salit J, Staudt MR, Ahmed J, et al. Persistence of smoking-induced dysregulation of miRNA expression in the small airway epithelium despite smoking cessation. PLoS One. 2015; 10:e0120824.

13. Rock JR, Randell SH, Hogan BL. Airway basal stem cells: a perspective on their roles in epithelial homeostasis and remodeling. Dis Model Mech. 2010; 3:545–556.

14. Puchelle E, Zahm JM, Tournier JM, Coraux C. Airway epithelial repair, regeneration, and remodeling after injury in chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2006; 3:726–733.

15. Crystal RG. Airway basal cells. The "smoking gun" of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2014; 190:1355–1362.

16. Shaykhiev R, Crystal RG. Early events in the pathogenesis of chronic obstructive pulmonary disease: smoking-induced reprogramming of airway epithelial basal progenitor cells. Ann Am Thorac Soc. 2014; 11:Suppl 5. S252–S258.

17. Cosio MG, Majo J, Cosio MG. Inflammation of the airways and lung parenchyma in COPD: role of T cells. Chest. 2002; 121:5 Suppl. 160S–165S.

18. Rovina N, Koutsoukou A, Koulouris NG. Inflammation and immune response in COPD: where do we stand? Mediators Inflamm. 2013; 2013:413735.

19. Keller IE, Vosyka O, Takenaka S, Kloss A, Dahlmann B, Willems LI, et al. Regulation of immunoproteasome function in the lung. Sci Rep. 2015; 5:10230.

20. Curtis JL, Freeman CM, Hogg JC. The immunopathogenesis of chronic obstructive pulmonary disease: insights from recent research. Proc Am Thorac Soc. 2007; 4:512–521.

21. Soriano JB, Agusti A. The yin and yang of COPD: or balancing repair (yang) and inflammation (yin). Eur Respir J. 2008; 32:1426–1427.

22. Hogg JC, Timens W. The pathology of chronic obstructive pulmonary disease. Annu Rev Pathol. 2009; 4:435–459.

23. Givi ME, Peck MJ, Boon L, Mortaz E. The role of dendritic cells in the pathogenesis of cigarette smoke-induced emphysema in mice. Eur J Pharmacol. 2013; 721:259–266.

24. Kim V, Oros M, Durra H, Kelsen S, Aksoy M, Cornwell WD, et al. Chronic bronchitis and current smoking are associated with more goblet cells in moderate to severe COPD and smokers without airflow obstruction. PLoS One. 2015; 10:e0116108.

25. Ramos FL, Krahnke JS, Kim V. Clinical issues of mucus accumulation in COPD. Int J Chron Obstruct Pulmon Dis. 2014; 9:139–150.

26. Celli BR. Predictors of mortality in COPD. Respir Med. 2010; 104:773–779.

27. Murugan V, Peck MJ. Signal transduction pathways linking the activation of alveolar macrophages with the recruitment of neutrophils to lungs in chronic obstructive pulmonary disease. Exp Lung Res. 2009; 35:439–485.

28. Barnes PJ. Alveolar macrophages in chronic obstructive pulmonary disease (COPD). Cell Mol Biol (Noisy-le-grand). 2004; 50 Online Pub:OL627–OL637.

29. Hiemstra PS. Altered macrophage function in chronic obstructive pulmonary disease. Ann Am Thorac Soc. 2013; 10:S180–S185.

30. Holloway RA, Donnelly LE. Immunopathogenesis of chronic obstructive pulmonary disease. Curr Opin Pulm Med. 2013; 19:95–102.

31. Gordon S, Martinez FO. Alternative activation of macrophages: mechanism and functions. Immunity. 2010; 32:593–604.

32. Liu YC, Zou XB, Chai YF, Yao YM. Macrophage polarization in inflammatory diseases. Int J Biol Sci. 2014; 10:520–529.

33. Kunz LI, Lapperre TS, Snoeck-Stroband JB, Budulac SE, Timens W, van Wijngaarden S, et al. Smoking status and antiinflammatory macrophages in bronchoalveolar lavage and induced sputum in COPD. Respir Res. 2011; 12:34.

34. Shaykhiev R, Krause A, Salit J, Strulovici-Barel Y, Harvey BG, O'Connor TP, et al. Smoking-dependent reprogramming of alveolar macrophage polarization: implication for pathogenesis of chronic obstructive pulmonary disease. J Immunol. 2009; 183:2867–2883.

35. Churg A, Wang RD, Tai H, Wang X, Xie C, Dai J, et al. Macrophage metalloelastase mediates acute cigarette smokeinduced inflammation via tumor necrosis factor-alpha release. Am J Respir Crit Care Med. 2003; 167:1083–1089.

36. Culpitt SV, Rogers DF, Shah P, De Matos C, Russell RE, Donnelly LE, et al. Impaired inhibition by dexamethasone of cytokine release by alveolar macrophages from patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2003; 167:24–31.

37. Bozinovski S, Seow HJ, Chan SP, Anthony D, McQualter J, Hansen M, et al. Innate cellular sources of interleukin-17A regulate macrophage accumulation in cigarette- smoke-induced lung inflammation in mice. Clin Sci (Lond). 2015; 129:785–796.

38. Voss M, Wolf L, Kamyschnikow A, Wonnenberg B, Honecker A, Herr C, et al. IL-17A contributes to maintenance of pulmonary homeostasis in a murine model of cigarette smoke-induced emphysema. Am J Physiol Lung Cell Mol Physiol. 2015; 309:L188–L195.

39. Maneechotesuwan K, Wongkajornsilp A, Adcock IM, Barnes PJ. Simvastatin suppresses airway IL-17 and upregulates IL-10 in patients with stable COPD. Chest. 2015; 148:1164–1176.

40. Young RP, Hopkins R, Eaton TE. Pharmacological actions of statins: potential utility in COPD. Eur Respir Rev. 2009; 18:222–232.

41. Davis BB, Zeki AA, Bratt JM, Wang L, Filosto S, Walby WF, et al. Simvastatin inhibits smoke-induced airway epithelial injury: implications for COPD therapy. Eur Respir J. 2013; 42:350–361.

42. Kim SE, Thanh Thuy TT, Lee JH, Ro JY, Bae YA, Kong Y, et al. Simvastatin inhibits induction of matrix metalloproteinase-9 in rat alveolar macrophages exposed to cigarette smoke extract. Exp Mol Med. 2009; 41:277–287.

43. Criner GJ, Connett JE, Aaron SD, Albert RK, Bailey WC, Casaburi R, et al. Simvastatin for the prevention of exacerbations in moderate-to-severe COPD. N Engl J Med. 2014; 370:2201–2210.

44. Kaczmarek P, Sladek K, Skucha W, Rzeszutko M, Iwaniec T, Dziedzina S, et al. The influence of simvastatin on selected inflammatory markers in patients with chronic obstructive pulmonary disease. Pol Arch Med Wewn. 2010; 120:11–17.

45. Ingebrigtsen TS, Marott JL, Nordestgaard BG, Lange P, Hallas J, Vestbo J. Statin use and exacerbations in individuals with chronic obstructive pulmonary disease. Thorax. 2015; 70:33–40.

46. Ingebrigtsen T, Marott J, Nordestgaard B, Lange P, Hallas J, Vestbo J. Statin use and risk of exacerbations in individuals with COPD: the Copenhagen general population study. Eur Respir J. 2014; 44:Suppl 58. 426.

47. Wang MT, Lo YW, Tsai CL, Chang LC, Malone DC, Chu CL, et al. Statin use and risk of COPD exacerbation requiring hospitalization. Am J Med. 2013; 126:598–606.e2.

48. Condon TV, Sawyer RT, Fenton MJ, Riches DW. Lung dendritic cells at the innate-adaptive immune interface. J Leukoc Biol. 2011; 90:883–895.

49. Chabaud M, Heuze ML, Bretou M, Vargas P, Maiuri P, Solanes P, et al. Cell migration and antigen capture are antagonistic processes coupled by myosin II in dendritic cells. Nat Commun. 2015; 6:7526.

50. Van Pottelberge GR, Bracke KR, Joos GF, Brusselle GG. The role of dendritic cells in the pathogenesis of COPD: liaison officers in the front line. COPD. 2009; 6:284–290.

51. Vassallo R, Walters PR, Lamont J, Kottom TJ, Yi ES, Limper AH. Cigarette smoke promotes dendritic cell accumulation in COPD: a Lung Tissue Research Consortium study. Respir Res. 2010; 11:45.

52. Givi ME, Redegeld FA, Folkerts G, Mortaz E. Dendritic cells in pathogenesis of COPD. Curr Pharm Des. 2012; 18:2329–2335.

53. Tsoumakidou M, Bouloukaki I, Koutala H, Kouvidi K, Mitrouska I, Zakynthinos S, et al. Decreased sputum mature dendritic cells in healthy smokers and patients with chronic obstructive pulmonary disease. Int Arch Allergy Immunol. 2009; 150:389–397.

54. Brusselle GG, Joos GF, Bracke KR. New insights into the immunology of chronic obstructive pulmonary disease. Lancet. 2011; 378:1015–1026.

55. Wang X, Zhang C, Huang G, Han D, Guo Y, Meng X, et al. Resveratrol inhibits dysfunction of dendritic cells from chronic obstructive pulmonary disease patients through promoting miR-34. Int J Clin Exp Pathol. 2015; 8:5145–5152.

56. Silva AM, Oliveira MI, Sette L, Almeida CR, Oliveira MJ, Barbosa MA, et al. Resveratrol as a natural anti-tumor necrosis factor-alpha molecule: implications to dendritic cells and their crosstalk with mesenchymal stromal cells. PLoS One. 2014; 9:e91406.

57. Tsai YF, Hwang TL. Neutrophil elastase inhibitors: a patent review and potential applications for inflammatory lung diseases (2010-2014). Expert Opin Ther Pat. 2015; 25:1145–1158.

58. Lucas SD, Costa E, Guedes RC, Moreira R. Targeting COPD: advances on low-molecular-weight inhibitors of human neutrophil elastase. Med Res Rev. 2013; 33:Suppl 1. E73–E101.

59. Guyot N, Wartelle J, Malleret L, Todorov AA, Devouassoux G, Pacheco Y, et al. Unopposed cathepsin G, neutrophil elastase, and proteinase 3 cause severe lung damage and emphysema. Am J Pathol. 2014; 184:2197–2210.

60. Kosikowska P, Lesner A. Inhibitors of cathepsin G: a patent review (2005 to present). Expert Opin Ther Pat. 2013; 23:1611–1624.

61. Maryanoff BE, de Garavilla L, Greco MN, Haertlein BJ, Wells GI, Andrade-Gordon P, et al. Dual inhibition of cathepsin G and chymase is effective in animal models of pulmonary inflammation. Am J Respir Crit Care Med. 2010; 181:247–253.

62. Sinden NJ, Stockley RA. Proteinase 3 activity in sputum from subjects with alpha-1-antitrypsin deficiency and COPD. Eur Respir J. 2013; 41:1042–1050.

63. Rooney CP, Taggart C, Coakley R, McElvaney NG, O'Neill SJ. Anti-proteinase 3 antibody activation of neutrophils can be inhibited by alpha1-antitrypsin. Am J Respir Cell Mol Biol. 2001; 24:747–754.

64. Owen CA. Roles for proteinases in the pathogenesis of chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2008; 3:253–268.

65. Churg A, Zhou S, Wright JL. Series "matrix metalloproteinases in lung health and disease": matrix metalloproteinases in COPD. Eur Respir J. 2012; 39:197–209.

66. Papakonstantinou E, Karakiulakis G, Batzios S, Savic S, Roth M, Tamm M, et al. Acute exacerbations of COPD are associated with significant activation of matrix metalloproteinase 9 irrespectively of airway obstruction, emphysema and infection. Respir Res. 2015; 16:78.

67. Grzela K, Litwiniuk M, Zagorska W, Grzela T. Airway remodeling in chronic obstructive pulmonary disease and asthma: the role of matrix metalloproteinase-9. Arch Immunol Ther Exp (Warsz). 2015; 06. 28. [Epub]. DOI: 10.1007/s00005-015-0345-y.

68. Dahl R, Titlestad I, Lindqvist A, Wielders P, Wray H, Wang M, et al. Effects of an oral MMP-9 and -12 inhibitor, AZD1236, on biomarkers in moderate/severe COPD: a randomised controlled trial. Pulm Pharmacol Ther. 2012; 25:169–177.

69. Taylan M, Demir M, Kaya H, Selimoglu Sen H, Abakay O, Carkanat AI, et al. Alterations of the neutrophil-lymphocyte ratio during the period of stable and acute exacerbation of chronic obstructive pulmonary disease patients. Clin Respir J. 2015; 06. 19. [Epub]. DOI: 10.1111/crj.12336.

70. Gunay E, Sarinc Ulasli S, Akar O, Ahsen A, Gunay S, Koyuncu T, et al. Neutrophil-to-lymphocyte ratio in chronic obstructive pulmonary disease: a retrospective study. Inflammation. 2014; 37:374–380.

71. Glader P, von Wachenfeldt K, Lofdahl CG. Systemic CD4+ T-cell activation is correlated with FEV1 in smokers. Respir Med. 2006; 100:1088–1093.

72. Roos-Engstrand E, Ekstrand-Hammarstrom B, Pourazar J, Behndig AF, Bucht A, Blomberg A. Influence of smoking cessation on airway T lymphocyte subsets in COPD. COPD. 2009; 6:112–120.

73. Saetta M, Baraldo S, Turato G, Beghe B, Casoni GL, Bellettato CM, et al. Increased proportion of CD8+ T-lymphocytes in the paratracheal lymph nodes of smokers with mild COPD. Sarcoidosis Vasc Diffuse Lung Dis. 2003; 20:28–32.

74. Roos-Engstrand E, Pourazar J, Behndig AF, Blomberg A, Bucht A. Cytotoxic T cells expressing the co-stimulatory receptor NKG2 D are increased in cigarette smoking and COPD. Respir Res. 2010; 11:128.

75. Freeman CM, Han MK, Martinez FJ, Murray S, Liu LX, Chensue SW, et al. Cytotoxic potential of lung CD8(+) T cells increases with chronic obstructive pulmonary disease severity and with in vitro stimulation by IL-18 or IL-15. J Immunol. 2010; 184:6504–6513.

76. Tetley TD. Inflammatory cells and chronic obstructive pulmonary disease. Curr Drug Targets Inflamm Allergy. 2005; 4:607–618.

77. Maeno T, Houghton AM, Quintero PA, Grumelli S, Owen CA, Shapiro SD. CD8+ T cells are required for inflammation and destruction in cigarette smoke-induced emphysema in mice. J Immunol. 2007; 178:8090–8096.

78. Hodge G, Mukaro V, Reynolds PN, Hodge S. Role of increased CD8/CD28(null) T cells and alternative co-stimulatory molecules in chronic obstructive pulmonary disease. Clin Exp Immunol. 2011; 166:94–102.

79. Hodge G, Jersmann H, Tran HB, Holmes M, Reynolds PN, Hodge S. Lymphocyte senescence in COPD is associated with loss of glucocorticoid receptor expression by proinflammatory/ cytotoxic lymphocytes. Respir Res. 2015; 16:2.

80. Hodge G, Holmes M, Jersmann H, Reynolds PN, Hodge S. Targeting peripheral blood pro-inflammatory cytotoxic lymphocytes by inhibiting CD137 expression: novel potential treatment for COPD. BMC Pulm Med. 2014; 14:85.

81. Gadgil A, Duncan SR. Role of T-lymphocytes and proinflammatory mediators in the pathogenesis of chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2008; 3:531–541.

82. Wang H, Peng W, Weng Y, Ying H, Li H, Xia D, et al. Imbalance of Th17/Treg cells in mice with chronic cigarette smoke exposure. Int Immunopharmacol. 2012; 14:504–512.

83. Feghali-Bostwick CA, Gadgil AS, Otterbein LE, Pilewski JM, Stoner MW, Csizmadia E, et al. Autoantibodies in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2008; 177:156–163.

84. Lambers C, Hacker S, Posch M, Hoetzenecker K, Pollreisz A, Lichtenauer M, et al. T cell senescence and contraction of T cell repertoire diversity in patients with chronic obstructive pulmonary disease. Clin Exp Immunol. 2009; 155:466–475.

85. Angulo M, Lecuona E, Sznajder JI. Role of MicroRNAs in lung disease. Arch Bronconeumol. 2012; 48:325–330.

86. De Smet EG, Mestdagh P, Vandesompele J, Brusselle GG, Bracke KR. Non-coding RNAs in the pathogenesis of COPD. Thorax. 2015; 70:782–791.

87. Rupani H, Sanchez-Elsner T, Howarth P. MicroRNAs and respiratory diseases. Eur Respir J. 2013; 41:695–705.

88. Ezzie ME, Crawford M, Cho JH, Orellana R, Zhang S, Gelinas R, et al. Gene expression networks in COPD: microRNA and mRNA regulation. Thorax. 2012; 67:122–131.

89. Savarimuthu Francis SM, Davidson MR, Tan ME, Wright CM, Clarke BE, Duhig EE, et al. MicroRNA-34c is associated with emphysema severity and modulates SERPINE1 expression. BMC Genomics. 2014; 15:88.

90. Van Pottelberge GR, Mestdagh P, Bracke KR, Thas O, van Durme YM, Joos GF, et al. MicroRNA expression in induced sputum of smokers and patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2011; 183:898–906.

91. Barnes PJ. Corticosteroid resistance in airway disease. Proc Am Thorac Soc. 2004; 1:264–268.

92. Di Stefano A, Caramori G, Ricciardolo FL, Capelli A, Adcock IM, Donner CF. Cellular and molecular mechanisms in chronic obstructive pulmonary disease: an overview. Clin Exp Allergy. 2004; 34:1156–1167.

93. Barnes PJ, Adcock IM. Glucocorticoid resistance in inflammatory diseases. Lancet. 2009; 373:1905–1917.

94. Barnes PJ. Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2013; 131:636–645.

95. Yang M, Kumar RK, Foster PS. Pathogenesis of steroid-resistant airway hyperresponsiveness: interaction between IFNgamma and TLR4/MyD88 pathways. J Immunol. 2009; 182:5107–5115.

96. Li JJ, Wang W, Baines KJ, Bowden NA, Hansbro PM, Gibson PG, et al. IL-27/IFN-gamma induce MyD88-dependent steroid-resistant airway hyperresponsiveness by inhibiting glucocorticoid signaling in macrophages. J Immunol. 2010; 185:4401–4409.

97. Barnes PJ. The cytokine network in asthma and chronic obstructive pulmonary disease. J Clin Invest. 2008; 118:3546–3556.

98. Torvinen M, Campwala H, Kilty I. The role of IFN-gamma in regulation of IFN-gamma-inducible protein 10 (IP-10) expression in lung epithelial cell and peripheral blood mononuclear cell co-cultures. Respir Res. 2007; 8:80.

99. Southworth T, Metryka A, Lea S, Farrow S, Plumb J, Singh D. IFN-gamma synergistically enhances LPS signalling in alveolar macrophages from COPD patients and controls by corticosteroid-resistant STAT1 activation. Br J Pharmacol. 2012; 166:2070–2083.

100. Goleva E, Li LB, Leung DY. IFN-gamma reverses IL-2- and IL-4-mediated T-cell steroid resistance. Am J Respir Cell Mol Biol. 2009; 40:223–230.

101. Kaur M, Smyth LJ, Cadden P, Grundy S, Ray D, Plumb J, et al. T lymphocyte insensitivity to corticosteroids in chronic obstructive pulmonary disease. Respir Res. 2012; 13:20.