Skip to main content

Cellular Mechanisms of Allergic Airway Inflammation

  • Chapter
  • First Online:
Advances in Asthma

Abstract

Asthma has long been considered to be driven by allergen-specific T helper 2 (Th2) responses. Although Th2 cytokines produced by Th2 cells play a central role in the induction and regulation of airway inflammation, clinical and basic studies have begun to shed light on the role of many types of cells. It is now well recognized that asthma is a multicellular disease, involving abnormal responses of many different cell types in the lung, including airway structural cells and innate and adaptive immune cells. A subpopulation of CD4+ T cells, such as Th1, Th17, and regulatory T cells (Tregs), has also been implicated in the regulation of airway inflammation. Airway epithelial cells and dendritic cells play an important role in promoting innate and adaptive immune responses in asthma. Group 2 innate lymphoid cells (ILC2s) stimulated by epithelial cell-derived cytokines, IL-25, IL-33, and thymic stromal lymphopoietin (TSLP), produce Th2 cytokines and have been reported to be involved in the induction of airway inflammation. Complementary experimental approaches including cultured cells, animal models, and human clinical studies have provided many insights into diverse cellular mechanisms in this complex disease.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 139.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. de Boer WI, Sharma HS, Baelemans SM, Hoogsteden HC, Lambrecht BN, Braunstahl GJ. Altered expression of epithelial junctional proteins in atopic asthma: possible role in inflammation. Can J Physiol Pharmacol. 2008;86(3):105–12. https://doi.org/10.1139/y08-004.

    Article  PubMed  Google Scholar 

  2. Shahana S, Bjornsson E, Ludviksdottir D, Janson C, Nettelbladt O, Venge P, et al. Ultrastructure of bronchial biopsies from patients with allergic and non-allergic asthma. Respir Med. 2005;99(4):429–43. https://doi.org/10.1016/j.rmed.2004.08.013.

    Article  CAS  PubMed  Google Scholar 

  3. Georas SN, Rezaee F. Epithelial barrier function: at the front line of asthma immunology and allergic airway inflammation. J Allergy Clin Immunol. 2014;134(3):509–20. https://doi.org/10.1016/j.jaci.2014.05.049.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ziegler SF. Thymic stromal lymphopoietin and allergic disease. J Allergy Clin Immunol. 2012;130(4):845–52. https://doi.org/10.1016/j.jaci.2012.07.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Grotenboer NS, Ketelaar ME, Koppelman GH, Nawijn MC. Decoding asthma: translating genetic variation in IL33 and IL1RL1 into disease pathophysiology. J Allergy Clin Immunol. 2013;131(3):856–65. https://doi.org/10.1016/j.jaci.2012.11.028.

    Article  CAS  PubMed  Google Scholar 

  6. Prefontaine D, Nadigel J, Chouiali F, Audusseau S, Semlali A, Chakir J, et al. Increased IL-33 expression by epithelial cells in bronchial asthma. J Allergy Clin Immunol. 2010;125(3):752–4. https://doi.org/10.1016/j.jaci.2009.12.935.

    Article  CAS  PubMed  Google Scholar 

  7. Shikotra A, Choy DF, Ohri CM, Doran E, Butler C, Hargadon B, et al. Increased expression of immunoreactive thymic stromal lymphopoietin in patients with severe asthma. J Allergy Clin Immunol. 2012;129(1):104–11.e1. https://doi.org/10.1016/j.jaci.2011.08.031.

    Article  CAS  PubMed  Google Scholar 

  8. Tamari M, Tanaka S, Hirota T. Genome-wide association studies of allergic diseases. Allergol Int. 2013;62(1):21–8. https://doi.org/10.2332/allergolint.13-RAI-0539.

    Article  CAS  PubMed  Google Scholar 

  9. Christianson CA, Goplen NP, Zafar I, Irvin C, Good JT Jr, Rollins DR, et al. Persistence of asthma requires multiple feedback circuits involving type 2 innate lymphoid cells and IL-33. J Allergy Clin Immunol. 2015;136(1):59–68.e14. https://doi.org/10.1016/j.jaci.2014.11.037.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Sharma K. IL-18 attenuates experimental choroidal neovascularization as a potential therapy for wet age-related macular degeneration. Sci Transl Med 6, 230ra44 (2014). Ann Neurosci. 2014;21(4):150. https://doi.org/10.5214/ans.0972.7531.210407.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Halim TY, Krauss RH, Sun AC, Takei F. Lung natural helper cells are a critical source of Th2 cell-type cytokines in protease allergen-induced airway inflammation. Immunity. 2012;36(3):451–63. https://doi.org/10.1016/j.immuni.2011.12.020.

    Article  CAS  PubMed  Google Scholar 

  12. Barlow JL, Bellosi A, Hardman CS, Drynan LF, Wong SH, Cruickshank JP, et al. Innate IL-13-producing nuocytes arise during allergic lung inflammation and contribute to airways hyperreactivity. J Allergy Clin Immunol. 2012;129(1):191–8.e1. https://doi.org/10.1016/j.jaci.2011.09.041.

    Article  CAS  PubMed  Google Scholar 

  13. Price AE, Liang HE, Sullivan BM, Reinhardt RL, Eisley CJ, Erle DJ, et al. Systemically dispersed innate IL-13-expressing cells in type 2 immunity. Proc Natl Acad Sci U S A. 2010;107(25):11489–94. https://doi.org/10.1073/pnas.1003988107.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Barlow JL, Peel S, Fox J, Panova V, Hardman CS, Camelo A, et al. IL-33 is more potent than IL-25 in provoking IL-13-producing nuocytes (type 2 innate lymphoid cells) and airway contraction. J Allergy Clin Immunol. 2013;132(4):933–41. https://doi.org/10.1016/j.jaci.2013.05.012.

    Article  CAS  PubMed  Google Scholar 

  15. Hui CC, Murphy DM, Neighbour H, Al-Sayegh M, O'Byrne S, Thong B, et al. T cell-mediated induction of thymic stromal lymphopoietin in differentiated human primary bronchial epithelial cells. Clin Exp Allergy. 2014;44(7):953–64. https://doi.org/10.1111/cea.12330.

    Article  CAS  PubMed  Google Scholar 

  16. Boushey HA, Holtzman MJ, Sheller JR, Nadel JA. Bronchial hyperreactivity. Am Rev Respir Dis. 1980;121(2):389–413. https://doi.org/10.1164/arrd.1980.121.2.389.

    Article  CAS  PubMed  Google Scholar 

  17. Locksley RM. Asthma and allergic inflammation. Cell. 2010;140(6):777–83. https://doi.org/10.1016/j.cell.2010.03.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Grunig G, Warnock M, Wakil AE, Venkayya R, Brombacher F, Rennick DM, et al. Requirement for IL-13 independently of IL-4 in experimental asthma. Science. 1998;282(5397):2261–3.

    Article  CAS  Google Scholar 

  19. Kibe A, Inoue H, Fukuyama S, Machida K, Matsumoto K, Koto H, et al. Differential regulation by glucocorticoid of interleukin-13-induced eosinophilia, hyperresponsiveness, and goblet cell hyperplasia in mouse airways. Am J Respir Crit Care Med. 2003;167(1):50–6. https://doi.org/10.1164/rccm.2110084.

    Article  PubMed  Google Scholar 

  20. Goto K, Chiba Y, Matsusue K, Hattori Y, Maitani Y, Sakai H, et al. The proximal STAT6 and NF-kappaB sites are responsible for IL-13- and TNF-alpha-induced RhoA transcriptions in human bronchial smooth muscle cells. Pharmacol Res. 2010;61(5):466–72. https://doi.org/10.1016/j.phrs.2009.12.001.

    Article  CAS  PubMed  Google Scholar 

  21. Seki Y, Inoue H, Nagata N, Hayashi K, Fukuyama S, Matsumoto K, et al. SOCS-3 regulates onset and maintenance of T(H)2-mediated allergic responses. Nat Med. 2003;9(8):1047–54. https://doi.org/10.1038/nm896.

    Article  PubMed  Google Scholar 

  22. Fukuyama S, Nakano T, Matsumoto T, Oliver BG, Burgess JK, Moriwaki A, et al. Pulmonary suppressor of cytokine signaling-1 induced by IL-13 regulates allergic asthma phenotype. Am J Respir Crit Care Med. 2009;179(11):992–8. https://doi.org/10.1164/rccm.200806-992OC.

    Article  CAS  PubMed  Google Scholar 

  23. Sahoo SK, Shaikh SA, Sopariwala DH, Bal NC, Periasamy M. Sarcolipin protein interaction with sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) is distinct from phospholamban protein, and only sarcolipin can promote uncoupling of the SERCA pump. J Biol Chem. 2013;288(10):6881–9. https://doi.org/10.1074/jbc.M112.436915.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Grainge CL, Lau LC, Ward JA, Dulay V, Lahiff G, Wilson S, et al. Effect of bronchoconstriction on airway remodeling in asthma. N Engl J Med. 2011;364(21):2006–15. https://doi.org/10.1056/NEJMoa1014350.

    Article  CAS  PubMed  Google Scholar 

  25. Bates EE, Dieu MC, Ravel O, Zurawski SM, Patel S, Bridon JM, et al. CD40L activation of dendritic cells down-regulates DORA, a novel member of the immunoglobulin superfamily. Mol Immunol. 1998;35(9):513–24.

    Article  CAS  Google Scholar 

  26. Hammad H, Chieppa M, Perros F, Willart MA, Germain RN, Lambrecht BN. House dust mite allergen induces asthma via Toll-like receptor 4 triggering of airway structural cells. Nat Med. 2009;15(4):410–6. https://doi.org/10.1038/nm.1946.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. van Rijt LS, Prins JB, Leenen PJ, Thielemans K, de Vries VC, Hoogsteden HC, et al. Allergen-induced accumulation of airway dendritic cells is supported by an increase in CD31(hi)Ly-6C(neg) bone marrow precursors in a mouse model of asthma. Blood. 2002;100(10):3663–71. https://doi.org/10.1182/blood-2002-03-0673.

    Article  CAS  PubMed  Google Scholar 

  28. Sung S, Rose CE, Fu SM. Intratracheal priming with ovalbumin- and ovalbumin 323-339 peptide-pulsed dendritic cells induces airway hyperresponsiveness, lung eosinophilia, goblet cell hyperplasia, and inflammation. J Immunol. 2001;166(2):1261–71.

    Article  CAS  Google Scholar 

  29. van Rijt LS, Jung S, Kleinjan A, Vos N, Willart M, Duez C, et al. In vivo depletion of lung CD11c+ dendritic cells during allergen challenge abrogates the characteristic features of asthma. J Exp Med. 2005;201(6):981–91. https://doi.org/10.1084/jem.20042311.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ito T, Wang YH, Duramad O, Hori T, Delespesse GJ, Watanabe N, et al. TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand. J Exp Med. 2005;202(9):1213–23. https://doi.org/10.1084/jem.20051135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. So T, Song J, Sugie K, Altman A, Croft M. Signals from OX40 regulate nuclear factor of activated T cells c1 and T cell helper 2 lineage commitment. Proc Natl Acad Sci U S A. 2006;103(10):3740–5. https://doi.org/10.1073/pnas.0600205103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Colley T, Mercado N, Kunori Y, Brightling C, Bhavsar PK, Barnes PJ, et al. Defective sirtuin-1 increases IL-4 expression through acetylation of GATA-3 in patients with severe asthma. J Allergy Clin Immunol. 2016;137(5):1595–7.e7. https://doi.org/10.1016/j.jaci.2015.10.013.

    Article  CAS  PubMed  Google Scholar 

  33. Robinson DS, Hamid Q, Ying S, Tsicopoulos A, Barkans J, Bentley AM, et al. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N Engl J Med. 1992;326(5):298–304. https://doi.org/10.1056/nejm199201303260504.

    Article  CAS  PubMed  Google Scholar 

  34. Kim HY, DeKruyff RH, Umetsu DT. The many paths to asthma: phenotype shaped by innate and adaptive immunity. Nat Immunol. 2010;11(7):577–84. https://doi.org/10.1038/ni.1892.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Fulkerson PC, Rothenberg ME. Targeting eosinophils in allergy, inflammation and beyond. Nat Rev Drug Discov. 2013;12(2):117–29. https://doi.org/10.1038/nrd3838.

    Article  CAS  PubMed  Google Scholar 

  36. Randolph DA, Stephens R, Carruthers CJ, Chaplin DD. Cooperation between Th1 and Th2 cells in a murine model of eosinophilic airway inflammation. J Clin Invest. 1999;104(8):1021–9. https://doi.org/10.1172/jci7631.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hayashi N, Yoshimoto T, Izuhara K, Matsui K, Tanaka T, Nakanishi K. T helper 1 cells stimulated with ovalbumin and IL-18 induce airway hyperresponsiveness and lung fibrosis by IFN-gamma and IL-13 production. Proc Natl Acad Sci U S A. 2007;104(37):14765–70. https://doi.org/10.1073/pnas.0706378104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Motomura Y, Kitamura H, Hijikata A, Matsunaga Y, Matsumoto K, Inoue H, et al. The transcription factor E4BP4 regulates the production of IL-10 and IL-13 in CD4+ T cells. Nat Immunol. 2011;12(5):450–9. https://doi.org/10.1038/ni.2020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kudo M, Melton AC, Chen C, Engler MB, Huang KE, Ren X, et al. IL-17A produced by alphabeta T cells drives airway hyper-responsiveness in mice and enhances mouse and human airway smooth muscle contraction. Nat Med. 2012;18(4):547–54. https://doi.org/10.1038/nm.2684.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Barczyk A, Pierzchala W, Sozanska E. Interleukin-17 in sputum correlates with airway hyperresponsiveness to methacholine. Respir Med. 2003;97(6):726–33.

    Article  CAS  Google Scholar 

  41. Chatenoud L. Natural and induced T CD4+CD25+FOXP3+ regulatory T cells. Methods Mol Biol. 2011;677:3–13. https://doi.org/10.1007/978-1-60761-869-0_1.

    Article  CAS  PubMed  Google Scholar 

  42. Shevach EM. Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity. 2009;30(5):636–45. https://doi.org/10.1016/j.immuni.2009.04.010.

    Article  CAS  PubMed  Google Scholar 

  43. Sakaguchi S, Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T. Regulatory T cells: how do they suppress immune responses? Int Immunol. 2009;21(10):1105–11. https://doi.org/10.1093/intimm/dxp095.

    Article  CAS  PubMed  Google Scholar 

  44. Akdis M, Verhagen J, Taylor A, Karamloo F, Karagiannidis C, Crameri R, et al. Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells. J Exp Med. 2004;199(11):1567–75. https://doi.org/10.1084/jem.20032058.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hartl D, Koller B, Mehlhorn AT, Reinhardt D, Nicolai T, Schendel DJ, et al. Quantitative and functional impairment of pulmonary CD4+CD25hi regulatory T cells in pediatric asthma. J Allergy Clin Immunol. 2007;119(5):1258–66. https://doi.org/10.1016/j.jaci.2007.02.023.

    Article  CAS  PubMed  Google Scholar 

  46. Spits H, Di Santo JP. The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling. Nat Immunol. 2011;12(1):21–7. https://doi.org/10.1038/ni.1962.

    Article  CAS  PubMed  Google Scholar 

  47. Wilhelm C, Hirota K, Stieglitz B, Van Snick J, Tolaini M, Lahl K, et al. An IL-9 fate reporter demonstrates the induction of an innate IL-9 response in lung inflammation. Nat Immunol. 2011;12(11):1071–7. https://doi.org/10.1038/ni.2133.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Constantinides MG, McDonald BD, Verhoef PA, Bendelac A. A committed precursor to innate lymphoid cells. Nature. 2014;508(7496):397–401. https://doi.org/10.1038/nature13047.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Mjosberg J, Bernink J, Golebski K, Karrich JJ, Peters CP, Blom B, et al. The transcription factor GATA3 is essential for the function of human type 2 innate lymphoid cells. Immunity. 2012;37(4):649–59. https://doi.org/10.1016/j.immuni.2012.08.015.

    Article  CAS  PubMed  Google Scholar 

  50. Klein Wolterink RG, Kleinjan A, van Nimwegen M, Bergen I, de Bruijn M, Levani Y, et al. Pulmonary innate lymphoid cells are major producers of IL-5 and IL-13 in murine models of allergic asthma. Eur J Immunol. 2012;42(5):1106–16. https://doi.org/10.1002/eji.201142018.

    Article  CAS  PubMed  Google Scholar 

  51. Smith SG, Chen R, Kjarsgaard M, Huang C, Oliveria JP, O’Byrne PM, et al. Increased numbers of activated group 2 innate lymphoid cells in the airways of patients with severe asthma and persistent airway eosinophilia. J Allergy Clin Immunol. 2016;137(1):75–86.e8. https://doi.org/10.1016/j.jaci.2015.05.037.

    Article  CAS  PubMed  Google Scholar 

  52. Drake LY, Iijima K, Kita H. Group 2 innate lymphoid cells and CD4+ T cells cooperate to mediate type 2 immune response in mice. Allergy. 2014;69(10):1300–7. https://doi.org/10.1111/all.12446.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Mirchandani AS, Besnard AG, Yip E, Scott C, Bain CC, Cerovic V, et al. Type 2 innate lymphoid cells drive CD4+ Th2 cell responses. J Immunol. 2014;192(5):2442–8. https://doi.org/10.4049/jimmunol.1300974.

    Article  CAS  PubMed  Google Scholar 

  54. Kabata H, Moro K, Fukunaga K, Suzuki Y, Miyata J, Masaki K, et al. Thymic stromal lymphopoietin induces corticosteroid resistance in natural helper cells during airway inflammation. Nat Commun. 2013;4:2675. https://doi.org/10.1038/ncomms3675.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hiromasa Inoue .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Takagi, K., Machida, K., Inoue, H. (2019). Cellular Mechanisms of Allergic Airway Inflammation. In: Yokoyama, A. (eds) Advances in Asthma. Respiratory Disease Series: Diagnostic Tools and Disease Managements. Springer, Singapore. https://doi.org/10.1007/978-981-13-2790-2_3

Download citation

  • DOI: https://doi.org/10.1007/978-981-13-2790-2_3

  • Published:

  • Publisher Name: Springer, Singapore

  • Print ISBN: 978-981-13-2789-6

  • Online ISBN: 978-981-13-2790-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics