Allergy Asthma Respir Dis.  2014 Nov;2(5):317-325. 10.4168/aard.2014.2.5.317.

Innate immunity in asthma

• Kim HY

• KMID: 1803537
• DOI: http://doi.org/10.4168/aard.2014.2.5.317

Abstract

Asthma is a complex and heterogeneous disease with several phenotypes. Most studies have focused on allergic asthma associated with allergen sensitization and adaptive immunity. On the other hand, nonallergic asthma is associated with a number of environmental factors such as infection, air pollution, or obesity, and requires innate immunity rather than adaptive immunity. In the lung, a number of innate immune cells and mechanisms have evolved to lead lung inflammation and asthma. These innate mechanisms include innate cytokines and various innate cells, including innate lymphoid cells, natural killer cells, as well as gammadelta T cells, which together produce a wide range of cytokines, independent of adaptive immunity and conventional antigens. Here, we review the most recent works regarding innate immune cells and the mechanisms underlying their role in asthma.

Keyword

Airway hyperreactivity; Innate immunity; Innate lymphoid cells; Natural killer T cells; Gammadelta T cells

MeSH Terms

Adaptive Immunity
Air Pollution
Asthma*
Cytokines
Hand
Immunity, Innate*
Killer Cells, Natural
Lung
Lymphocytes
Natural Killer T-Cells
Obesity
Phenotype
Pneumonia
T-Lymphocytes
Cytokines

Figure

• 

  Fig. 1 The key clinical features (lung function, symptoms and exacerbations) and characteristic of asthma.

• 

  Fig. 2 The role of innate lymphoid cells (ILCs) in the development of allergic asthma. IL, interleukin; TSLP, thymic stromal lymphopoietin; DC, dendritic cell.

• 

  Fig. 3 The role of innate lymphoid cells (ILCs) in the development of nonallergic asthma. IL, interleukin; TSLP, thymic stromal lymphopoietin; IFN, interferon.

Reference

1. 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; 326:298–304.

2. Kim HY, DeKruyff RH, Umetsu DT. The many paths to asthma: phenotype shaped by innate and adaptive immunity. Nat Immunol. 2010; 11:577–584.

3. Chang YJ, Kim HY, Albacker LA, Baumgarth N, McKenzie AN, Smith DE, et al. Innate lymphoid cells mediate influenza-induced airway hyper-reactivity independently of adaptive immunity. Nat Immunol. 2011; 12:631–638.

4. Johnston RA, Zhu M, Rivera-Sanchez YM, Lu FL, Theman TA, Flynt L, et al. Allergic airway responses in obese mice. Am J Respir Crit Care Med. 2007; 176:650–658.

5. Pichavant M, Goya S, Meyer EH, Johnston RA, Kim HY, Matangkasombut P, et al. Ozone exposure in a mouse model induces airway hyperreactivity that requires the presence of natural killer T cells and IL-17. J Exp Med. 2008; 205:385–393.

6. Kim HY, Lee HJ, Chang YJ, Pichavant M, Shore SA, Fitzgerald KA, et al. Interleukin-17-producing innate lymphoid cells and the NLRP3 inflammasome facilitate obesity-associated airway hyperreactivity. Nat Med. 2014; 20:54–61.

7. Schuijs MJ, Willart MA, Hammad H, Lambrecht BN. Cytokine targets in airway inflammation. Curr Opin Pharmacol. 2013; 13:351–361.

8. 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; 15:410–416.

9. Willart MA, Deswarte K, Pouliot P, Braun H, Beyaert R, Lambrecht BN, et al. Interleukin-1α controls allergic sensitization to inhaled house dust mite via the epithelial release of GM-CSF and IL-33. J Exp Med. 2012; 209:1505–1517.

10. Ramadas RA, Li X, Shubitowski DM, Samineni S, Wills-Karp M, Ewart SL. IL-1 Receptor antagonist as a positional candidate gene in a murine model of allergic asthma. Immunogenetics. 2006; 58:851–855.

11. Schmitz N, Kurrer M, Kopf M. The IL-1 receptor 1 is critical for Th2 cell type airway immune responses in a mild but not in a more severe asthma model. Eur J Immunol. 2003; 33:991–1000.

12. Caucig P, Teschner D, Dinges S, Maxeiner JH, Reuter S, Finotto S, et al. Dual role of interleukin-1alpha in delayed-type hypersensitivity and airway hyperresponsiveness. Int Arch Allergy Immunol. 2010; 152:303–312.

13. Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E, Heath S, et al. A large-scale, consortium-based genomewide association study of asthma. N Engl J Med. 2010; 363:1211–1221.

14. Kurowska-Stolarska M, Stolarski B, Kewin P, Murphy G, Corrigan CJ, Ying S, et al. IL-33 amplifies the polarization of alternatively activated macrophages that contribute to airway inflammation. J Immunol. 2009; 183:6469–6477.

15. Moro K, Yamada T, Tanabe M, Takeuchi T, Ikawa T, Kawamoto H, et al. Innate production of T(H)2 cytokines by adipose tissue-associated c-Kit(+)Sca-1(+) lymphoid cells. Nature. 2010; 463:540–544.

16. Saglani S, Lui S, Ullmann N, Campbell GA, Sherburn RT, Mathie SA, et al. IL-33 promotes airway remodeling in pediatric patients with severe steroid-resistant asthma. J Allergy Clin Immunol. 2013; 132:676–685.e13.

17. Kaiko GE, Phipps S, Angkasekwinai P, Dong C, Foster PS. NK cell deficiency predisposes to viral-induced Th2-type allergic inflammation via epithelial-derived IL-25. J Immunol. 2010; 185:4681–4690.

18. 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; 129:191–198.e1-4.

19. Bernink JH, Peters CP, Munneke M, te Velde AA, Meijer SL, Weijer K, et al. Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues. Nat Immunol. 2013; 14:221–229.

20. Korsgren M, Persson CG, Sundler F, Bjerke T, Hansson T, Chambers BJ, et al. Natural killer cells determine development of allergen-induced eosinophilic airway inflammation in mice. J Exp Med. 1999; 189:553–562.

21. Klose CS, Flach M, Mohle L, Rogell L, Hoyler T, Ebert K, et al. Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages. Cell. 2014; 157:340–356.

22. Fort MM, Cheung J, Yen D, Li J, Zurawski SM, Lo S, et al. IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity. 2001; 15:985–995.

23. Fallon PG, Ballantyne SJ, Mangan NE, Barlow JL, Dasvarma A, Hewett DR, et al. Identification of an interleukin (IL)-25-dependent cell population that provides IL-4, IL-5, and IL-13 at the onset of helminth expulsion. J Exp Med. 2006; 203:1105–1116.

24. Allakhverdi Z, Comeau MR, Smith DE, Toy D, Endam LM, Desrosiers M, et al. CD34+ hemopoietic progenitor cells are potent effectors of allergic inflammation. J Allergy Clin Immunol. 2009; 123:472–478.

25. Saenz SA, Siracusa MC, Perrigoue JG, Spencer SP, Urban JF Jr, Tocker JE, et al. IL25 elicits a multipotent progenitor cell population that promotes T(H)2 cytokine responses. Nature. 2010; 464:1362–1366.

26. Neill DR, Wong SH, Bellosi A, Flynn RJ, Daly M, Langford TK, et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature. 2010; 464:1367–1370.

27. Spits H, Cupedo T. Innate lymphoid cells: emerging insights in development, lineage relationships, and function. Annu Rev Immunol. 2012; 30:647–675.

28. Halim TY, MacLaren A, Romanish MT, Gold MJ, McNagny KM, Takei F. Retinoic-acid-receptor-related orphan nuclear receptor alpha is required for natural helper cell development and allergic inflammation. Immunity. 2012; 37:463–474.

29. Wong SH, Walker JA, Jolin HE, Drynan LF, Hams E, Camelo A, et al. Transcription factor RORα is critical for nuocyte development. Nat Immunol. 2012; 13:229–236.

30. Zhou L. Striking similarity: GATA-3 regulates ILC2 and Th2 cells. Immunity. 2012; 37:589–591.

31. Spooner CJ, Lesch J, Yan D, Khan AA, Abbas A, Ramirez-Carrozzi V, et al. Specification of type 2 innate lymphocytes by the transcriptional determinant Gfi1. Nat Immunol. 2013; 14:1229–1236.

32. Sanos SL, Bui VL, Mortha A, Oberle K, Heners C, Johner C, et al. ROR-gammat and commensal microflora are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells. Nat Immunol. 2009; 10:83–91.

33. Possot C, Schmutz S, Chea S, Boucontet L, Louise A, Cumano A, et al. Notch signaling is necessary for adult, but not fetal, development of RORγt(+) innate lymphoid cells. Nat Immunol. 2011; 12:949–958.

34. Serafini N, Klein Wolterink RG, Satoh-Takayama N, Xu W, Vosshenrich CA, Hendriks RW, et al. Gata3 drives development of RORγt+ group 3 innate lymphoid cells. J Exp Med. 2014; 211:199–208.

35. Sonnenberg GF, Monticelli LA, Elloso MM, Fouser LA, Artis D. CD4(+) lymphoid tissue-inducer cells promote innate immunity in the gut. Immunity. 2011; 34:122–134.

36. Tumanov AV, Koroleva EP, Guo X, Wang Y, Kruglov A, Nedospasov S, et al. Lymphotoxin controls the IL-22 protection pathway in gut innate lymphoid cells during mucosal pathogen challenge. Cell Host Microbe. 2011; 10:44–53.

37. Kearley J, Buckland KF, Mathie SA, Lloyd CM. Resolution of allergic inflammation and airway hyperreactivity is dependent upon disruption of the T1/ST2-IL-33 pathway. Am J Respir Crit Care Med. 2009; 179:772–781.

38. 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; 12:1071–1077.

39. 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; 36:451–463.

40. Bartemes KR, Iijima K, Kobayashi T, Kephart GM, McKenzie AN, Kita H. IL-33-responsive lineage- CD25+ CD44(hi) lymphoid cells mediate innate type 2 immunity and allergic inflammation in the lungs. J Immunol. 2012; 188:1503–1513.

41. Monticelli LA, Sonnenberg GF, Abt MC, Alenghat T, Ziegler CG, Doering TA, et al. Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nat Immunol. 2011; 12:1045–1054.

42. Moore WC, Meyers DA, Wenzel SE, Teague WG, Li H, Li X, et al. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med. 2010; 181:315–323.

43. Schnyder-Candrian S, Togbe D, Couillin I, Mercier I, Brombacher F, Quesniaux V, et al. Interleukin-17 is a negative regulator of established allergic asthma. J Exp Med. 2006; 203:2715–2725.

44. McKinley L, Alcorn JF, Peterson A, Dupont RB, Kapadia S, Logar A, et al. TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice. J Immunol. 2008; 181:4089–4097.

45. Kudo M, Melton AC, Chen C, Engler MB, Huang KE, Ren X, et al. IL-17A produced by αβ T cells drives airway hyper-responsiveness in mice and enhances mouse and human airway smooth muscle contraction. Nat Med. 2012; 18:547–554.

46. Spencer SP, Wilhelm C, Yang Q, Hall JA, Bouladoux N, Boyd A, et al. Adaptation of innate lymphoid cells to a micronutrient deficiency promotes type 2 barrier immunity. Science. 2014; 343:432–437.

47. Bendelac A, Savage PB, Teyton L. The biology of NKT cells. Annu Rev Immunol. 2007; 25:297–336.

48. Meyer EH, Goya S, Akbari O, Berry GJ, Savage PB, Kronenberg M, et al. Glycolipid activation of invariant T cell receptor+ NK T cells is sufficient to induce airway hyperreactivity independent of conventional CD4+ T cells. Proc Natl Acad Sci U S A. 2006; 103:2782–2787.

49. Albacker LA, Chaudhary V, Chang YJ, Kim HY, Chuang YT, Pichavant M, et al. Invariant natural killer T cells recognize a fungal glycosphingolipid that can induce airway hyperreactivity. Nat Med. 2013; 19:1297–1304.

50. Agea E, Russano A, Bistoni O, Mannucci R, Nicoletti I, Corazzi L, et al. Human CD1-restricted T cell recognition of lipids from pollens. J Exp Med. 2005; 202:295–308.

51. Wingender G, Rogers P, Batzer G, Lee MS, Bai D, Pei B, et al. Invariant NKT cells are required for airway inflammation induced by environmental antigens. J Exp Med. 2011; 208:1151–1162.

52. Kim HY, Chang YJ, Chuang YT, Lee HH, Kasahara DI, Martin T, et al. T-cell immunoglobulin and mucin domain 1 deficiency eliminates airway hyperreactivity triggered by the recognition of airway cell death. J Allergy Clin Immunol. 2013; 132:414–425.e6.

53. Olszak T, An D, Zeissig S, Vera MP, Richter J, Franke A, et al. Microbial exposure during early life has persistent effects on natural killer T cell function. Science. 2012; 336:489–493.

54. Ege MJ, Mayer M, Normand AC, Genuneit J, Cookson WO, Braun-Fahrländer C, et al. Exposure to environmental microorganisms and childhood asthma. N Engl J Med. 2011; 364:701–709.

55. Carding SR, Egan PJ. Gammadelta T cells: functional plasticity and heterogeneity. Nat Rev Immunol. 2002; 2:336–345.

56. Skeen MJ, Ziegler HK. Activation of gamma delta T cells for production of IFN-gamma is mediated by bacteria via macrophage-derived cytokines IL-1 and IL-12. J Immunol. 1995; 154:5832–5841.

57. Sutton CE, Lalor SJ, Sweeney CM, Brereton CF, Lavelle EC, Mills KH. Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity. 2009; 31:331–341.

58. Zhang L, Liu J, Wang E, Wang B, Zeng S, Wu J, et al. Respiratory syncytial virus protects against the subsequent development of ovalbumin-induced allergic responses by inhibiting Th2-type γδ T cells. J Med Virol. 2013; 85:149–156.

59. Glanville N, Message SD, Walton RP, Pearson RM, Parker HL, Laza-Stanca V, et al. γδT cells suppress inflammation and disease during rhinovirus-induced asthma exacerbations. Mucosal Immunol. 2013; 6:1091–1100.