Immune Netw.  2014 Aug;14(4):171-181. 10.4110/in.2014.14.4.171.

The Roles of Innate Lymphoid Cells in the Development of Asthma

• Woo Y
• Jeong D
• Chung DH
• Kim HY

• KMID: 2150805
• DOI: http://doi.org/10.4110/in.2014.14.4.171

Abstract

Asthma is a common pulmonary disease with several different forms. The most studied form of asthma is the allergic form, which is mainly related to the function of Th2 cells and their production of cytokines (IL-4, IL-5, and IL-13) in association with allergen sensitization and adaptive immunity. Recently, there have been many advances in understanding non-allergic asthma, which seems to be related to environmental factors such as air pollution, infection, or even obesity. Cells of the innate immune system, including macrophages, neutrophils, and natural killer T cells as well as the newly described innate lymphoid cells, are effective producers of a variety of cytokines and seem to play important roles in the development of non-allergic asthma. In this review, we focus on recent findings regarding innate lymphoid cells and their roles in asthma.

Keyword

Airway hyperreactivity; Asthma; Innate lymphoid cells; Allergic asthma; Non-allergic asthma

MeSH Terms

Adaptive Immunity
Air Pollution
Asthma*
Cytokines
Immune System
Interleukin-5
Lung Diseases
Lymphocytes*
Macrophages
Natural Killer T-Cells
Neutrophils
Obesity
Th2 Cells
Cytokines
Interleukin-5

Figure

• 

  Figure 1 Schematic of innate lymphoid cell function in the development of asthma. Viruses (influenza A virus, rhinovirus, and respiratory syncytial virus), allergens (ovalbumin, human dust mite, papain, etc.), or excess nutrients induce lung epithelial cells to release various cytokines that can amplify the activation of subsets of innate lymphoid cells (ILCs). Release of IL-12 and IL-15 can induce the proliferation and activation of type 1 ILCs producing IFN-γ, which has an antiviral function. In response to IL-25 and IL-33, type 2 ILCs produce large amounts of IL-5, IL-9, and IL-13, which promote eosinophilia (IL-5), bronchial hyperresponsiveness (IL-9 and IL-13), smooth muscle cell contraction (IL-13), and goblet cell hyperplasia (IL-13). By producing various cytokines, ILCs can induce activation of downstream immune cells and intensify the symptoms of asthma.

Reference

1. Robinson DS, Hamid Q, Ying S, Tsicopoulos A, Barkans J, Bentley AM, Corrigan C, Durham SR, Kay AB. 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. Corren J, Lemanske RF, Hanania NA, Korenblat PE, Parsey MV, Arron JR, Harris JM, Scheerens H, Wu LC, Su Z, Mosesova S, Eisner MD, Bohen SP, Matthews JG. Lebrikizumab Treatment in Adults with Asthma. N Engl J Med. 2011; 365:1088–1098.

4. Johnston RA, Zhu M, Rivera-Sanchez YM, Lu FL, Theman TA, Flynt L, Shore SA. 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, Zhu M, Iwakura Y, Savage PB, DeKruyff RH, Shore SA, Umetsu DT. 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 EY, Battaile JT, Patel AC, You Y, Agapov E, Grayson MH, Benoit LA, Byers DE, Alevy Y, Tucker J, Swanson S, Tidwell R, Tyner JW, Morton JD, Castro M, Polineni D, Patterson GA, Schwendener RA, Allard JD, Peltz G, Holtzman MJ. Persistent activation of an innate immune response translates respiratory viral infection into chronic lung disease. Nat Med. 2008; 14:633–640.

7. Wright RJ. Stress and atopic disorders. J Allergy Clin Immunol. 2005; 116:1301–1306.

8. Moro K, Yamada T, Tanabe M, Takeuchi T, Ikawa T, Kawamoto H, Furusawa J, Ohtani M, Fujii H, Koyasu S. Innate production of T(H)2 cytokines by adipose tissue-associated c-Kit(+)Sca-1(+) lymphoid cells. Nature. 2010; 463:540–544.

9. Neill DR, Wong SH, Bellosi A, Flynn RJ, Daly M, Langford TK, Bucks C, Kane CM, Fallon PG, Pannell R, Jolin HE, McKenzie AN. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature. 2010; 464:1367–1370.

10. Buonocore S, Ahern PP, Uhlig HH, Ivanov II, Littman DR, Maloy KJ, Powrie F. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature. 2010; 464:1371–1375.

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

12. Kim HY, Lee HJ, Chang YJ, Pichavant M, Shore SA, Fitzgerald KA, Iwakura Y, Israel E, Bolger K, Faul J, DeKruyff RH, Umetsu DT. Interleukin-17-producing innate lymphoid cells and the NLRP3 inflammasome facilitate obesity-associated airway hyperreactivity. Nat Med. 2014; 20:54–61.

13. Monticelli LA, Sonnenberg GF, Abt MC, Alenghat T, Ziegler CG, Doering TA, Angelosanto JM, Laidlaw BJ, Yang CY, Sathaliyawala T, Kubota M, Turner D, Diamond JM, Goldrath AW, Farber DL, Collman RG, Wherry EJ, Artis D. Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nat Immunol. 2011; 12:1045–1054.

14. Spits H, Di Santo JP. The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling. Nat Immunol. 2011; 12:21–27.

15. Bernink J, Mjosberg J, Spits H. Th1- and Th2-like subsets of innate lymphoid cells. Immunol Rev. 2013; 252:133–138.

16. Strowig T, Brilot F, Munz C. Noncytotoxic functions of NK cells: direct pathogen restriction and assistance to adaptive immunity. J Immunol. 2008; 180:7785–7791.

17. Vivier E, Raulet DH, Moretta A, Caligiuri MA, Zitvogel L, Lanier LL, Yokoyama WM, Ugolini S. Innate or adaptive immunity? The example of natural killer cells. Science. 2011; 331:44–49.

18. 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.

19. Wong SH, Walker JA, Jolin HE, Drynan LF, Hams E, Camelo A, Barlow JL, Neill DR, Panova V, Koch U, Radtke F, Hardman CS, Hwang YY, Fallon PG, McKenzie AN. Transcription factor RORalpha is critical for nuocyte development. Nat Immunol. 2012; 13:229–236.

20. Hoyler T, Klose CS, Souabni A, Turqueti-Neves A, Pfeifer D, Rawlins EL, Voehringer D, Busslinger M, Diefenbach A. The transcription factor GATA-3 controls cell fate and maintenance of type 2 innate lymphoid cells. Immunity. 2012; 37:634–648.

21. 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.

22. Coccia M, Harrison OJ, Schiering C, Asquith MJ, Becher B, Powrie F, Maloy KJ. IL-1beta mediates chronic intestinal inflammation by promoting the accumulation of IL-17A secreting innate lymphoid cells and CD4(+) Th17 cells. J Exp Med. 2012; 209:1595–1609.

23. Kim HY, Lee HJ, Chang YJ, Pichavant M, Shore SA, Fitzgerald KA, Iwakura Y, Israel E, Bolger K, Faul J, DeKruyff RH, Umetsu DT. IL-17 producing innate lymphoid cells and the NLRP3 inflammasome facilitate obesity-associated airway hyperreactivity. Nat Med. 2013; doi: 10.1038/nm.3423.

24. Villanova F, Flutter B, Tosi I, Grys K, Sreeneebus H, Perera GK, Chapman A, Smith CH, Di Meglio P, Nestle FO. Characterization of innate lymphoid cells in human skin and blood demonstrates increase of NKp44⁺ ILC3 in psoriasis. J Invest Dermatol. 2014; 134:984–991.

25. Teunissen MB, Munneke JM, Bernink JH, Spuls PI, Res PC, Te Velde A, Cheuk S, Brouwer MW, Menting SP, Eidsmo L, Spits H, Hazenberg MD, Mjosberg J. Composition of Innate Lymphoid Cell Subsets in the Human Skin: Enrichment of NCR ILC3 in Lesional Skin and Blood of Psoriasis Patients. J Invest Dermatol. 2014; doi: 10.1038/jid.2014.146.

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

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

28. Satoh-Takayama N, Lesjean-Pottier S, Vieira P, Sawa S, Eberl G, Vosshenrich CA, Di Santo JP. IL-7 and IL-15 independently program the differentiation of intestinal CD3-NKp46⁺ cell subsets from Id2-dependent precursors. J Exp Med. 2010; 207:273–280.

29. Cherrier M, Sawa S, Eberl G. Notch, Id2, and RORγt sequentially orchestrate the fetal development of lymphoid tissue inducer cells. J Exp Med. 2012; 209:729–740.

30. Possot C. Notch signaling is necessary for adult, but not fetal, development of RORγt⁺ innate lymphoid cells. Nat Immunol. 2011; 12:949–958.

31. Hughes T, Briercheck EL, Freud AG, Trotta R, McClory S, Scoville SD, Keller K, Deng Y, Cole J, Harrison N, Mao C, Zhang J, Benson DM, Yu J, Caligiuri MA. The transcription factor AHR prevents the differentiation of a stage 3 innate lymphoid cell subset to natural killer cells. Cell Rep. 2014; doi: 10.1016/j.celrep.2014.05.042.

32. Klose CS, Flach M, Mohle L, Rogell L, Hoyler T, Ebert K, Fabiunke C, Pfeifer D, Sexl V, Fonseca-Pereira D, Domingues RG, Veiga-Fernandes H, Arnold SJ, Busslinger M, Dunay IR, Tanriver Y, Diefenbach A. Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages. Cell. 2014; 157:340–356.

33. Malhotra A, Shanker A. NK cells: immune cross-talk and therapeutic implications. Immunotherapy. 2011; 3:1143–1166.

34. Li F, Zhu H, Sun R, Wei H, Tian Z. Natural killer cells are involved in acute lung immune injury caused by respiratory syncytial virus infection. J Virol. 2012; 86:2251–2258.

35. Jayaraman A, Jackson DJ, Message SD, Pearson RM, Aniscenko J, Caramori G, Mallia P, Papi A, Shamji B, Edwards M, Westwick J, Hansel T, Stanciu LA, Johnston SL, Bartlett NW. IL-15 complexes induce NK- and T-cell responses independent of type I IFN signaling during rhinovirus infection. Mucosal Immunol. 2014; doi: 10.1038/mi.2014.2.

36. Korsgren M, Persson CG, Sundler F, Bjerke T, Hansson T, Chambers BJ, Hong S, Van Kaer L, Ljunggren HG, Korsgren O. Natural killer cells determine development of allergen-induced eosinophilic airway inflammation in mice. J Exp Med. 1999; 189:553–562.

37. Mathias CB, Guernsey LA, Zammit D, Brammer C, Wu CA, Thrall RS, Aguila HL. Pro-inflammatory role of natural killer cells in the development of allergic airway disease. Clin Exp Allergy. 2014; 44:589–601.

38. Farhadi N, Lambert L, Triulzi C, Openshaw PJ, Guerra N, Culley FJ. Natural killer cell NKG2D and granzyme B are critical for allergic pulmonary inflammation. J Allergy Clin Immunol. 2014; 133:827–835.

39. Fort MM, Cheung J, Yen D, Li J, Zurawski SM, Lo S, Menon S, Clifford T, Hunte B, Lesley R, Muchamuel T, Hurst SD, Zurawski G, Leach MW, Gorman DM, Rennick DM. IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity. 2001; 15:985–995.

40. Fallon PG, Ballantyne SJ, Mangan NE, Barlow JL, Dasvarma A, Hewett DR, McIlgorm A, Jolin HE, McKenzie AN. 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.

41. Allakhverdi Z, Comeau MR, Smith DE, Toy D, Endam LM, Desrosiers M, Liu YJ, Howie KJ, Denburg JA, Gauvreau GM, Delespesse G. CD34⁺ hemopoietic progenitor cells are potent effectors of allergic inflammation. J Allergy Clin Immunol. 2009; 123:472–478.

42. Saenz SA, Siracusa MC, Perrigoue JG, Spencer SP, Urban JF Jr, Tocker JE, Budelsky AL, Kleinschek MA, Kastelein RA, Kambayashi T, Bhandoola A, Artis D. IL25 elicits a multipotent progenitor cell population that promotes T(H)2 cytokine responses. Nature. 2010; 464:1362–1366.

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

44. Price AE, Liang HE, Sullivan BM, Reinhardt RL, Eisley CJ, Erle DJ, Locksley RM. Systemically dispersed innate IL-13-expressing cells in type 2 immunity. Proc Natl Acad Sci U S A. 2010; 107:11489–11494.

45. Hong JY, Bentley JK, Chung Y, Lei J, Steenrod JM, Chen Q, Sajjan US, Hershenson MB. Neonatal rhinovirus induces mucous metaplasia and airways hyperresponsiveness through IL-25 and type 2 innate lymphoid cells. J Allergy Clin Immunol. 2014; 134(2):429–439.

46. Blanken MO, Rovers MM, Molenaar JM, Winkler-Seinstra PL, Meijer A, Kimpen JL, Bont L. Dutch RSV Neonatal Network. Respiratory syncytial virus and recurrent wheeze in healthy preterm infants. N Engl J Med. 2013; 368:1791–1799.

47. Monticelli LA, Sonnenberg GF, Abt MC, Alenghat T, Ziegler CG, Doering TA, Angelosanto JM, Laidlaw BJ, Yang CY, Sathaliyawala T, Kubota M, Turner D, Diamond JM, Goldrath AW, Farber DL, Collman RG, Wherry EJ, Artis D. Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nat Immunol. 2011; doi: 10.1031/ni.2131.

48. 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.

49. Barlow JL, Bellosi A, Hardman CS, Drynan LF, Wong SH, Cruickshank JP, McKenzie AN. Innate IL-13-producing nuocytes arise during allergic lung inflammation and contribute to airways hyperreactivity. J Allergy Clin Immunol. 2012; 129:191–198.

50. 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.

51. Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, Zurawski G, Moshrefi M, Qin J, Li X, Gorman DM, Bazan JF, Kastelein RA. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity. 2005; 23:479–490.

52. Hurst SD, Muchamuel T, Gorman DM, Gilbert JM, Clifford T, Kwan S, Menon S, Seymour B, Jackson C, Kung TT, Brieland JK, Zurawski SM, Chapman RW, Zurawski G, Coffman RL. New IL-17 family members promote Th1 or Th2 responses in the lung: in vivo function of the novel cytokine IL-25. J Immunol. 2002; 169:443–453.

53. Klein Wolterink RG, Kleinjan A, van Nimwegen M, Bergen I, de Bruijn M, Levani Y, Hendriks RW. Pulmonary innate lymphoid cells are major producers of IL-5 and IL-13 in murine models of allergic asthma. Eur J Immunol. 2012; 42:1106–1116.

54. 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.

55. Wilhelm C, Hirota K, Stieglitz B, van Snick J, Tolaini M, Lahl K, Sparwasser T, Helmby H, Stockinger B. An IL-9 fate reporter demonstrates the induction of an innate IL-9 response in lung inflammation. Nat Immunol. 2011; 12:1071–1077.

56. Kurebayashi S, Ueda E, Sakaue M, Patel DD, Medvedev A, Zhang F, Jetten AM. Retinoid-related orphan receptor gamma (RORγ) is essential for lymphoid organogenesis and controls apoptosis during thymopoiesis. Proc Natl Acad Sci U S A. 2000; 97:10132–10137.

57. Eberl G, Marmon S, Sunshine MJ, Rennert PD, Choi Y, Littman DR. An essential function for the nuclear receptor RORt in the generation of fetal lymphoid tissue inducer cells. Nat Immunol. 2004; 5:64–73.

58. Mebius RE, Rennert P, Weissman IL. Developing lymph nodes collect CD4⁺CD3^- LTbeta⁺ cells that can differentiate to APC, NK cells, and follicular cells but not T or B cells. Immunity. 1997; 7:493–504.

59. Finke D. Fate and function of lymphoid tissue inducer cells. Curr Opin Immunol. 2005; 17:144–150.

60. Yoshida H, Honda K, Shinkura R, Adachi S, Nishikawa S, Maki K, Ikuta K, Nishikawa SI. IL-7 receptor alpha⁺ CD3(-) cells in the embryonic intestine induces the organizing center of Peyer's patches. Int Immunol. 1999; 11:643–655.

61. Sawa S, Lochner M, Satoh-Takayama N, Dulauroy S, Berard M, Kleinschek M, Cua D, Di Santo JP, Eberl G. RORγt⁺ innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota. Nat Immunol. 2011; 12:320–326.

62. Cupedo T, Crellin NK, Papazian N, Rombouts EJ, Weijer K, Grogan JL, Fibbe WE, Cornelissen JJ, Spits H. Human fetal lymphoid tissue-inducer cells are interleukin 17-producing precursors to RORC⁺ CD127⁺ natural killer-like cells. Nat Immunol. 2009; 10:66–74.

63. Geremia A, Arancibia-Carcamo CV, Fleming MP, Rust N, Singh B, Mortensen NJ, Travis SP, Powrie F. IL-23-responsive innate lymphoid cells are increased in inflammatory bowel disease. J Exp Med. 2011; 208:1127–1133.

64. Crellin NK, Trifari S, Kaplan CD, Satoh-Takayama N, Di Santo JP, Spits H. Regulation of cytokine secretion in human CD127(+) LTi-like innate lymphoid cells by Toll-like receptor 2. Immunity. 2010; 33:752–764.

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

66. Satoh-Takayama N, Vosshenrich CA, Lesjean-Pottier S, Sawa S, Lochner M, Rattis F, Mention JJ, Thiam K, Cerf-Bensussan N, Mandelboim O, Eberl G, Di Santo JP. Microbial flora drives interleukin 22 production in intestinal NKp46⁺ cells that provide innate mucosal immune defense. Immunity. 2008; 29:958–970.

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

68. Kudo M, Melton AC, Chen C, Engler MB, Huang KE, Ren X, Wang Y, Bernstein X, Li JT, Atabai K, Huang X, Sheppard D. 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; 18:547–554.

69. McKinley L, Alcorn JF, Peterson A, Dupont RB, Kapadia S, Logar A, Henry A, Irvin CG, Piganelli JD, Ray A, Kolls JK. TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice. J Immunol. 2008; 181:4089–4097.

70. Osborn O, Olefsky JM. The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med. 2012; 18:363–374.

71. Holguin F, Bleecker ER, Busse WW, Calhoun WJ, Castro M, Erzurum SC, Fitzpatrick AM, Gaston B, Israel E, Jarjour NN, Moore WC, Peters SP, Yonas M, Teague WG, Wenzel SE. Obesity and asthma: an association modified by age of asthma onset. J Allergy Clin Immunol. 2011; 127:1486–1493.

72. Camargo CA Jr, Weiss ST, Zhang S, Willett WC, Speizer FE. Prospective study of body mass index, weight change, and risk of adult-onset asthma in women. Arch Intern Med. 1999; 159:2582–2588.

73. Fuchs A, Vermi W, Lee JS, Lonardi S, Gilfillan S, Newberry RD, Cella M, Colonna M. Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-gamma-producing cells. Immunity. 2013; 38:769–781.

74. Bernink JH, Peters CP, Munneke M, te Velde AA, Meijer SL, Weijer K, Hreggvidsdottir HS, Heinsbroek SE, Legrand N, Buskens CJ, Bemelman WA, Mjosberg JM, Spits H. Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues. Nat Immunol. 2013; 14:221–229.

75. Prefontaine D, Lajoie-Kadoch S, Foley S, Audusseau S, Olivenstein R, Halayko AJ, Lemiere C, Martin JG, Hamid Q. Increased expression of IL-33 in severe asthma: evidence of expression by airway smooth muscle cells. J Immunol. 2009; 183:5094–5103.

76. Mjosberg JM, Trifari S, Crellin NK, Peters CP, van Drunen CM, Piet B, Fokkens WJ, Cupedo T, Spits H. Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161. Nat Immunol. 2011; 12:1055–1062.

77. Kwon BI, Hong S, Shin K, Choi EH, Hwang JJ, Lee SH. Innate type 2 immunity is associated with eosinophilic pleural effusion in primary spontaneous pneumothorax. Am J Respir Crit Care Med. 2013; 188:577–585.

78. Kim BS, Siracusa MC, Saenz SA, Noti M, Monticelli LA, Sonnenberg GF, Hepworth MR, van Voorhees AS, Comeau MR, Artis D D. TSLP elicits IL-33-independent innate lymphoid cell responses to promote skin inflammation. Sci Transl Med. 2013; 5:170ra16.

79. Nagarkar DR, Poposki JA, Tan BK, Comeau MR, Peters AT, Hulse KE, Suh LA, Norton J, Harris KE, Grammer LC, Chandra RK, Conley DB, Kern RC, Schleimer RP, Kato A. Thymic stromal lymphopoietin activity is increased in nasal polyps of patients with chronic rhinosinusitis. J Allergy Clin Immunol. 2013; 132:593–600.

80. Kamekura R, Kojima T, Takano K, Go M, Sawada N, Himi T. The role of IL-33 and its receptor ST2 in human nasal epithelium with allergic rhinitis. Clin Exp Allergy. 2012; 42:218–228.

81. Dyring-Andersen B, Geisler C, Agerbeck C, Lauritsen JP, Gudjonsdottir SD, Skov L, Bonefeld CM. Increased number and frequency of group 3 innate lymphoid cells in nonlesional psoriatic skin. Br J Dermatol. 2014; 170:609–616.