Advertisement

Role of Integrins α4 and β2 Onset and Development of Chronic Allergic Asthma in Mice

  • Ena Ray Banerjee
Chapter

Abstract

Objective. Chronic asthma is characterized by an ongoing recruitment of inflammatory cells and airway hyperresponsiveness leading to structural airway remodeling. Although α4b1 and β2 integrins regulate leukocyte migration in inflammatory diseases and play decisive roles in acute asthma, their role has not been explored under the chronic asthma setting. To extend our earlier studies with α4Δ/Δ and β2L/L mice, which showed that both α4 and β2 integrins have nonredundant regulatory roles in acute ovalbumin (OVA)-induced asthma, we explored to what extent these molecular pathways control development of structural airway remodeling in chronic asthma.

Materials and Methods. Control, α4Δ/Δ, and β2L/L mouse groups, sensitized by intraperitoneal OVA as allergen, received intratracheal OVA periodically over days 8–55 to induce a chronic asthma phenotype. Post-OVA assessment of inflammation and pulmonary function (airway hyperresponsiveness), together with airway modeling measured by goblet cell metaplasia, collagen content of lung, and transforming growth factor b1 expression in lung homogenates were evaluated.

Results. In contrast to control and β2L/L mice, α4Δ/Δ mice failed to develop and maintain the composite chronic asthma phenotype evaluated as mentioned, and subepithelial collagen content was comparable to baseline. These data indicate that β2 integrins, although required for inflammatory migration in acute asthma, are dispensable for structural remodeling in chronic asthma.

Conclusion. α4 integrins appear to have a regulatory role in directing transforming growth factor b-induced collagen deposition and structural alterations in lung architecture likely through interactions of Th2 cells, eosinophils, or mast cells with endothelium, resident airway cells, and/or extracellular matrix.

Keywords

Mast Cell Acute Asthma Airway Remodel Chronic Asthma Soluble Collagen 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Wills-Karp M. Immunologic basis of antigen-induced airway hyperresponsiveness. Annu Rev Immunol. 1999;17:255–81.PubMedCrossRefGoogle Scholar
  2. 2.
    Shum BO, Rolph MS, Sewell WA. Mechanisms in allergic airway inflammation-lessons from studies in the mouse. Expert Rev Mol Med. 2008;10:e15.PubMedCrossRefGoogle Scholar
  3. 3.
    Elias JA, Zhu Z, Chupp G, Homer RJ. Airway remodeling in asthma. J Clin Invest. 1999;104:1001–6.PubMedCrossRefGoogle Scholar
  4. 4.
    Kariyawasam HH, Robinson DS. The role of eosinophils in airway tissue remodelling in asthma. Curr Opin Immunol. 2007;19:681–6.PubMedCrossRefGoogle Scholar
  5. 5.
    Benayoun L, Druilhe A, Dombret M-C, Aubier M, Pretolani M. Airway structural alterations selectively associated with severe asthma. Am J Respir Crit Care Med. 2003;167:1360–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Ebina M, Takahashi T, Chiba T, Motomiya M. Cellular hypertrophy and hyperplasia of airway smooth muscles underlying bronchial asthma: a 3-d morphometric study. Am Rev Respir Dis. 1993;148:720–6.PubMedCrossRefGoogle Scholar
  7. 7.
    HoshinoM NY, Sim JJ. Expression of growth factors and remodeling of the airway wall in bronchial asthma. Thorax. 1998;53:21–7.CrossRefGoogle Scholar
  8. 8.
    Jeffery PK. Remodeling in asthma and chronic obstructive lung disease. Am J Respir Crit Care Med. 2001;164:28S–38.CrossRefGoogle Scholar
  9. 9.
    Payne DNR, Rogers AV, Adelroth E, et al. Early thickening of the reticular basement membrane in children with difficult asthma. Am J Respir Crit Care Med. 2003;167:78–82.PubMedCrossRefGoogle Scholar
  10. 10.
    Tanaka H, Yamada G, Saikai T, et al. Increased airway vascularity in newly diagnosed asthma using a high-magnification bronchovideoscope. Am J Respir Crit Care Med. 2003;168:1495–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Zhou L, Li J, Goldsmith AM, et al. Human bronchial smooth muscle cell lines show a hypertrophic phenotype typical of severe asthma. Am J Respir Crit Care Med. 2004;169:703–11.PubMedCrossRefGoogle Scholar
  12. 12.
    Epstein MM. Do mouse models of allergic asthma mimic clinical disease? Int Arch Allergy Immunol. 2004;133:84–100.PubMedCrossRefGoogle Scholar
  13. 13.
    Borchers MT, Crosby J, Farmer S, et al. Blockade of CD49d inhibits allergic airway pathologies independent of effects on leukocyte recruitment. Am J Physiol Lung Cell Mol Physiol. 2001;280:L813–21.PubMedGoogle Scholar
  14. 14.
    Chin JE, Hatfield CA, Winterrowd GE, et al. Airway recruitment of leukocytes in mice is dependent on alphα4-integrins and vascular cell adhesion molecule-1. Am J Physiol Lung Cell Mol Physiol. 1997;272:L219–29.Google Scholar
  15. 15.
    Henderson Jr WR, Chi EY, Albert RK, et al. Blockade of CD49d (alpha 4 integrin) on intrapulmonary but not circulating leukocytes inhibits airway inflammation and hyperresponsiveness in a mouse model of asthma. J Clin Invest. 1997;100:3083–92.PubMedCrossRefGoogle Scholar
  16. 16.
    Koo GC, Shah K, Ding GJF, et al. A small molecule very late antigen- 4 antagonist can inhibit ovalbumin-induced lung inflammation. Am J Respir Crit Care Med. 2003;167:1400–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Laberge S, Rabb H, Issekutz T, Martin J. Role of VLA-4 and LFA-1 in allergen-induced airway hyperresponsiveness and lung inflammation in the rat. Am J Respir Crit Care Med. 1995;151:822–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Nakajima H, Sano H, Nishimura T, Yoshida S, Iwamoto I. Role of vascular cell adhesion molecule 1/very late activation antigen 4 and intercellular adhesion molecule 1/lymphocyte function-associated antigen 1 interactions in antigen-induced eosinophil and T cell recruitment into the tissue. J Exp Med. 1994;179:1145–54.PubMedCrossRefGoogle Scholar
  19. 19.
    Lee S-H, Prince JE, Rais M, et al. Differential requirement for CD18 in T-helper effector homing. Nat Med. 2003;9:1281–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Kanwar S, Smith C, Shardonofsky F, Burns A. The role of MAC-1 (CD11b/CD18) in antigen-induced airway eosinophilia in mice. Am J Respir Cell Mol Biol. 2001;25:170–7.PubMedCrossRefGoogle Scholar
  21. 21.
    Schneider T, Issekutz TB, Issekutz AC. The role of alpha 4 (CD49d) and beta 2 (CD18) integrins in eosinophil and neutrophil migration to allergic lung inflammation in the brown Norway rat. Am J Respir Cell Mol Biol. 1999;20:448–57.PubMedCrossRefGoogle Scholar
  22. 22.
    Banerjee ER, Jiang Y, Henderson Jr WR, Scott LM, Papayannopoulou T. Alphα4 and beta2 integrins have nonredundant roles for asthma development, but for optimal allergen sensitization only alphα4 is critical. Exp Hematol. 2007;35:605–17.PubMedCrossRefGoogle Scholar
  23. 23.
    Barthel SR, Johansson MW, McNamee DM, Mosher DF. Roles of integrin activation in eosinophil function and the eosinophilic inflammation of asthma. J Leukoc Biol. 2008;83:1–12.PubMedCrossRefGoogle Scholar
  24. 24.
    Scott LM, Priestley GV, Papayannopoulou T. Deletion of alphα4 integrins from adult hematopoietic cells reveals roles in homeostasis, regeneration, and homing. Mol Cell Biol. 2003;23:9349–60.PubMedCrossRefGoogle Scholar
  25. 25.
    Lloyd C, Gutierrez-Ramos J. Animal models to study chemokine receptor function: in vivo mouse models of allergic airway inflammation. Methods Mol Biol. 2004;239:199–210.PubMedGoogle Scholar
  26. 26.
    Larbi KY, Allen AR, Tam FWK, et al. VCAM-1 has a tissue-specific role in mediating interleukin-4-induced eosinophil accumulation in rat models: evidence for a dissociation between endothelial-cell VCAM-1 expression and a functional role in eosinophil migration. Blood. 2000;96:3601–9.PubMedGoogle Scholar
  27. 27.
    Lobb R, Hemler M. The pathophysiologic role of alpha 4 integrins in vivo. J Clin Invest. 1994;94:1722–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Banerjee ER, Latchman YE, Jiang Y, Priestley GV, Papayannopoulou T. Distinct changes in adult lymphopoiesis in Rag2(−/−) mice fully reconstituted by alphα4-deficient adult bone marrow cells. Exp Hematol. 2008;36:1004–13.PubMedCrossRefGoogle Scholar
  29. 29.
    Moir LM, Burgess JK, Black JL. Transforming growth factor beta 1 increases fibronectin deposition through integrin receptor alpha 5 beta 1 on human airway smooth muscle. J Allergy Clin Immunol. 2008;121:1034–9. e1034.PubMedCrossRefGoogle Scholar
  30. 30.
    Takeda K, Haczku A, Lee J, Irvin C, Gelfand E. Strain dependence of airway hyperresponsiveness reflects differences in eosinophil localization in the lung. Am J Physiol Lung Cell Mol Physiol. 2001;281:L394–402.PubMedGoogle Scholar
  31. 31.
    Berlin AA, Hogaboam CM, Lukacs NW. Inhibition of SCF attenuates peribronchial remodeling in chronic cockroach allergen-induced asthma. Lab Invest. 2006;86:557–65.PubMedGoogle Scholar
  32. 32.
    Dolgachev V, Berlin AA, Lukacs NW. Eosinophil activation of fibroblasts from chronic allergen-induced disease utilizes stem cell factor for phenotypic changes. Am J Pathol. 2008;172:68–76.PubMedCrossRefGoogle Scholar
  33. 33.
    Kovach NL, Lin N, Yednock T, Harlan JM, Broudy VC. Stem cell factor modulates avidity of alpha 4 beta 1 and alpha 5 beta 1 integrins expressed on hematopoietic cell lines. Blood. 1995;85:159–67.PubMedGoogle Scholar
  34. 34.
    Al-Muhsen SZ, Shablovsky G, Olivenstein R, Mazer B, Hamid Q. The expression of stem cell factor and c-kit receptor in human asthmatic airways. Clin Exp Allergy. 2004;34:911–6.PubMedCrossRefGoogle Scholar
  35. 35.
    Tan BL, Yazicioglu MN, Ingram D, et al. Genetic evidence for convergence of c-kit- and alpha 4 integrin-mediated signals on class IA PI-3kinase and the Rac pathway in regulating integrin-directed migration in mast cells. Blood. 2003;101:4725–32.PubMedCrossRefGoogle Scholar
  36. 36.
    Reuter S, Taube C. Mast cells and the development of allergic airway disease. J Occup Med Toxicol. 2008;3 Suppl 1:S2.PubMedCrossRefGoogle Scholar
  37. 37.
    Abonia JP, Hallgren J, Jones T, et al. Alpha-4 integrins and VCAM-1, but not MAdCAM-1, are essential for recruitment of mast cell progenitors to the inflamed lung. Blood. 2006;108:1588–94.PubMedCrossRefGoogle Scholar
  38. 38.
    Gonzalo J-A, Qiu Y, Lora JM, et al. Coordinated involvement of mast cells and T cells in allergic mucosal inflammation: critical role of the CC chemokine ligand 1:CCR8 axis. J Immunol. 2007;179:1740–50.PubMedGoogle Scholar
  39. 39.
    Hojo M, Maghni K, Issekutz TB, Martin JG. Involvement of alpha −4 integrins in allergic airway responses and mast cell degranulation in vivo. Am J Respir Crit Care Med. 1998;158:1127–33.PubMedCrossRefGoogle Scholar
  40. 40.
    Harrington LE, Hatton RD, Mangan PR, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol. 2005;6:1123–32.PubMedCrossRefGoogle Scholar
  41. 41.
    Park H, Li Z, Yang XO, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005;6:1133–41.PubMedCrossRefGoogle Scholar
  42. 42.
    Song C, Luo L, Lei Z, et al. IL-17-producing alveolar macrophages mediate allergic lung inflammation related to asthma. J Immunol. 2008;181:6117–24.PubMedGoogle Scholar
  43. 43.
    Schnyder-Candrian S, Togbe D, Couillin I, et al. Interleukin-17 is a negative regulator of established allergic asthma. J Exp Med. 2006;203:2715–25.PubMedCrossRefGoogle Scholar
  44. 44.
    Lewkowich IP, Lajoie S, Clark JR, Herman NS, Sproles AA, Wills-Karp M. Allergen uptake, activation, and IL-23 production by pulmonary myeloid DCs drives airway hyperresponsiveness in asthma-susceptible mice. PLoS ONE. 2008;3:e3879.PubMedCrossRefGoogle Scholar
  45. 45.
    Jain D, Keslacy S, Tliba O, et al. Essential role of IFNbeta and CD38 in TNFalpha-induced airway smooth muscle hyper-responsiveness. Immunobiology. 2008;213:499–509.PubMedCrossRefGoogle Scholar
  46. 46.
    Kim BE, Leung DYM, Boguniewicz M, Howell MD. Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6. Clin Immunol. 2008;126:332.PubMedCrossRefGoogle Scholar
  47. 47.
    Kumar RK, Herbert C, Webb DC, Li L, Foster PS. Effects of anticytokine therapy in a mouse model of chronic asthma. Am J Respir Crit Care Med. 2004;170:1043–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Broide DH. Immunologic and inflammatory mechanisms that drive asthma progression to remodeling. J Allergy Clin Immunol. 2008;121:560–70.PubMedCrossRefGoogle Scholar
  49. 49.
    Lee CG, Homer RJ, Zhu Z, et al. Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor beta (1). J Exp Med. 2001;194:809–22.PubMedCrossRefGoogle Scholar
  50. 50.
    Nath P, Yee Leung S, Williams AS, et al. Complete inhibition of allergic airway inflammation and remodelling in quadruple IL-4/5/9/13 −/− mice. Clin Exp Allergy. 2007;37:1427–35.PubMedGoogle Scholar
  51. 51.
    Kumar RK, Herbert C, Yang M, Koskinen AML, McKenzie ANJ, Foster PS. Role of interleukin-13 in eosinophil accumulation and airway remodelling in a mouse model of chronic asthma. Clin Exp Allergy. 2002;32:1104–11.PubMedCrossRefGoogle Scholar
  52. 52.
    Lai W-Q, Goh HH, Bao Z, Wong WSF, Melendez AJ, Leung BP. The role of sphingosine kinase in a murine model of allergic asthma. J Immunol. 2008;180:4323–9.PubMedGoogle Scholar
  53. 53.
    Roth M, Johnson PRA, Borger P, et al. Dysfunctional interaction of C/EBP{alpha} and the glucocorticoid receptor in asthmatic bronchial smooth-muscle cells. N Engl J Med. 2004;351:560–74.PubMedCrossRefGoogle Scholar
  54. 54.
    Ulyanova T, Priestley G, Banerjee E, Papayannopoulou T. Unique and redundant roles of alphα4 and beta2 integrins in kinetics of recruitment of lymphoid vs myeloid cell subsets to the inflamed peritoneum revealed by studies of genetically deficient mice. Exp Hematol. 2007;35:1256–65.PubMedCrossRefGoogle Scholar
  55. 55.
    Koerner-Rettberg C, Doths S, Stroet A, Schwarze J. Reduced lung function in a chronic asthma model is associated with prolonged inflammation, but independent of peribronchial fibrosis. PLoS ONE. 2008;3:e1575.PubMedCrossRefGoogle Scholar
  56. 56.
    Iwata A, Nishio K, Winn RK, Chi EY, Henderson Jr WR, Harlan JM. A broad-spectrum caspase inhibitor attenuates allergic airway inflammation in murine asthma model. J Immunol. 2003;170:3386–91.PubMedGoogle Scholar
  57. 57.
    Henderson Jr WR, Chi EY, Maliszewski CR. Soluble IL-4 receptor inhibits airway inflammation following allergen challenge in a mouse model of asthma. J Immunol. 2000;164:1086–95.PubMedGoogle Scholar
  58. 58.
    Henderson Jr WR, Lewis DB, Albert RK, et al. The importance of leukotrienes in airway inflammation in a mouse model of asthma. J Exp Med. 1996;184:1483–94.PubMedCrossRefGoogle Scholar
  59. 59.
    Cho JY, Miller M, Baek KJ, et al. Inhibition of airway remodeling in IL-5-deficient mice. J Clin Invest. 2004;113:551–60.PubMedGoogle Scholar
  60. 60.
    Henderson Jr W, Banerjee E, Chi E. Differential effects of (s)- and (r)-enantiomers of albuterol in a mouse asthma model. J Allergy Clin Immunol. 2005;116:332–40.PubMedCrossRefGoogle Scholar

Published in

  1. –.
    Banerjee ER, Jiang Y, Henderson Jr WR, Latchman YL, Papayannopoulou T. Absence of α4 but not β2 integrins restrains the development of chronic allergic asthma using mouse genetic models. Exp Hematol. 2009;37:715–27.PubMedCrossRefGoogle Scholar

Copyright information

© Springer India 2014

Authors and Affiliations

  • Ena Ray Banerjee
    • 1
  1. 1.Immunology & Regenerative Medicine Research UnitUniversity College of Science, Technology and AgricultureKolkataIndia

Personalised recommendations