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The role of IL-33/ST2, IL-4, and eosinophils on the airway hyperresponsiveness induced by Strongyloides venezuelensis in BALB/c mice


Strongyloidiasis is a neglected chronic nematode infection, in which the control of autoinfection rate and severity of disease is dependent on type 2 immune responses. Strongyloides also causes Th2 responses in the lung of infected animals and changes in airway function, including airway hyperresponsiveness (AHR). Mechanisms of AHR during Strongyloides venezuelensis infection are not entirely known, and we investigate here the role of IL-4, eosinophils, and IL-33/ST2. AHR was evaluated in infected mice by determining changes in lung function after increasing doses of methacholine. Balb/C, but no C57Bl/6, mice developed AHR, tissue eosinophilia, and increased local IL-4 and IL-5 production. Functional changes peaked at day 4 and 7, after the larva had left the lungs. AHR was clearly dependent on IL-4 but not on eosinophils, as evaluated by experiments in IL-4 and Gata-1-deficient mice. Experiments in ST2-deficient mice showed that this pathway was not needed for induction of AHR but was necessary for the maintenance of AHR and for Th2 responses in the lung. These studies clearly show a crucial role for IL-4 in the induction of AHR following S. venezuelensis infection and for IL-33/ST2 in maintaining AHR and lung Th2 responses.

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  1. Akiho H, Blennerhassett P, Deng Y, Collins SM (2002) Role of IL-4, IL-13, and STAT6 in inflammation-induced hypercontractility of murine smooth muscle cells. Am J Physiol Gastrointest Liver Physiol 282:G226–G232

  2. Alcântara-Neves NM, Badaró SJ, dos Santos MC, Pontes-de-Carvalho L, Barreto ML (2010) The presence of serum anti-Ascaris lumbricoides IgE antibodies and of Trichuris trichiura infection are risk factors for wheezing and/or atopy in preschool-aged Brazilian children. Respir Res 11:114–122

  3. Allen JE, Maizels RM (1996) Immunology of human helminth infection. Int Arch Allergy Immunol 109:3–10

  4. Bønnelykke K, Sleiman P, Nielsen K, Kreiner-Møller E, Mercader JM, Belgrave D, den Dekker HT, Husby A, Sevelsted A, Faura-Tellez G, Mortensen LJ, Paternoster L, Flaaten R, Mølgaard A, Smart DE, Thomsen PF, Rasmussen MA, Bonàs-Guarch S, Holst C, Nohr EA, Yadav R, March ME, Blicher T, Lackie PM, Jaddoe VW, Simpson A, Holloway JW, Duijts L, Custovic A, Davies DE, Torrents D, Gupta R, Hollegaard MV, Hougaard DM, Hakonarson H, Bisgaard H (2014) A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations. Nat Genet 46:51–55

  5. Brightling CE, Bradding P, Symon FA, Holgate ST, Wardlaw AJ, Pavord D (2002) Mast cell infiltration of airway smooth muscle in asthma. N Engl J Med 346:1699–1705

  6. Cadman ET, Thysse KA, Bearder S, Cheung AY, Johnston AC, Lee JJ, Lawrence RA (2014) Eosinophils are important for protection, immunoregulation and pathology during infection with nematode microfilariae. PLoS Pathog 10(3), e1003988

  7. Carrol NG, Mutavdzic S, James AL (2002) Increased mast cells and neutrophils in submucosal mucous glands and mucus plugging in patients with asthma. Thorax 57:677–682

  8. Cliffe LJ, Humphreys NE, Lane TE, Potten CS, Booth C, Grencis RK (2005) Accelerated intestinal epithelial cell turnover: a new mechanism of parasite expulsion. Science 308:1463–1465

  9. Coyle AJ, Köhler G, Tsuyuki S, Brombacher F, Kopf M (1998) Eosinophils are not required to induce airway hyperreponsiveness after nematode infection. Eur J Immunol 28:2640–2647

  10. Coyle AJ, Lloyd C, Tian J et al (1999) Crucial role of the interleukin 1 receptor family member T1/ST2 in T helper cell type 2-mediated lung mucosal immune responses. J Exp Med 190:895–902

  11. Darby M, Schnoeller C, Vira A, Culley FJ, Bobat S, Logan E, Kirstein F, Wess J, Cunningham AF, Brombacher F, Selkirk ME, Horsnell WG (2015) The M3 muscarinic receptor is required for optimal adaptive immunity to helminth and bacterial infection. PLoS Pathog 11(1):e1004636

  12. Ferreira CM, Pereira AT, de Souza RS, Cassali GD, Souza DG, Lemos VS, Teixeira MM, Negrão-Corrêa D (2007) Prevention of changes in airway function facilities Strongyloides venezuelensis infection in rats. Microbes Infect 9:813–820

  13. Ferreira CM, Pereira ATM, Souza RS, Coelho FM, Poole S, Teixeira MM, Negrão-Corrêa D (2010) Role of IL-13 in a model of Strongyloides venezuelensis infection in rats. Microbes Infect 12:409–414

  14. Finkelman FD, Shea-Donohue T, Goldhill J, Sullivan CA, Morris SC, Madden KB, Gause WC, Urban JF Jr (1997) Cytokine regulation of host defense against parasitic gastronintestinal nematodes: lessons from studies with rodent models. Annu Rev Immunol 15:505–533

  15. Fux M, Pecaric-Petkovic T, Odermatt A, Hausmann OV, Lorentz A, Bischoff SC, Virchow JC, Dahinden CA (2013) IL-33 is a mediator rather than a trigger of the acute allergic response in humans. Allergy 69:216–222

  16. Gueders MM, Paulissen G, Crahay C, Quesada-Calvo F, Hacha J, Van Hove C, Tournoy K, Louis R, Foidart JM, Noël A, Cataldo DD (2009) Mouse models of asthma: a comparison between C57BL/6 and BALB/c strains regarding bronchial responsiveness, inflammation, and cytokine production. Inflamm Res 58:845–854

  17. Hall LR, Mehlotra RK, Higgins AW, Haxhiu MA, Pearlman E (1998) An essential role for interleukin-5 and eosinophils in helminth-induced airway hyperresponsiveness. Infect Immun 66:4425–4551

  18. Hirota JA, Ask K, Fritz D, Ellis R, Wattie J, Richards CD, Labiris R, Kolb M, Inman MD (2009) Role of STAT6 and SMAD2 in a model of chronic allergen exposure: a mouse strain comparison study. Clin Exp Allergy 39:147–158

  19. Horsnell WG, Cutler AJ, Hoving JC, Mearns H, Myburgh E, Arendse B, Finkelman FD, Owens GK, Erle D, Brombacher F (2007) Delayed goblet cell hyperplasia, acetylcholine receptor expression, and worm expulsion in SMC-specific IL-4Rα-deficient mice. PLoS Pathog 3:46–53

  20. Hotez PJ, Brindley PJ, Bethony JM, King CH, Pearce EJ, Jacobson J (2008) Helminth infections: the great neglected tropical diseases. J Clin Invest 118:1311–1321

  21. Humbles AA, Lloyd CM, McMillan SJ et al (2004) A critical role for eosinophils in allergic airways remodeling. Science 305:1776–1779

  22. Ikutani M, Yanagibashi T, Ogasawara M, Tsuneyama K, Yamamoto S, Hattori Y, Kouro T, Itakura A, Nagai Y, Takaki S, Takatsu K (2012) Identification of innate IL-5-producing cells and their role in lung eosinophil regulation and anti-tumor immunity. J Immunol 188:703–713

  23. Kasaian MT, Miller DK (2008) IL-13 as a therapeutic target for respiratory disease. Biochem Pharmacol 76:147–155

  24. Khan WI, Collins SM (2004) Immune-mediated alteration in gut physiology and its role in host defence in nematode infection. Parasite Immunol 26:319–326

  25. Kim HY, Chang YJ, Subramanian S, Lee HH, Albacker LA, Matangkasombut P, Savage PB, McKenzie AN, Smith DE, Rottman JB, DeKruyff RH, Umetsu DT (2012) Innate lymphoid cells responding to IL-33 mediate airway hyperreactivity independently of adaptative immunity. J Allergy Clin Immunol 129:216–227

  26. Kobayashi I, Horii Y (2008) Gastrointestinal motor disturbance in rabbits experimentally infected with Strongyloides papillosus. Vet Parasitol 158:67–72

  27. Kondo Y, Yoshimoto T, Yasuda K, Futatsugi-Yumikura S, Morimoto M, Hayashi N, Hoshino T, Fujimoto J, Nakanishi K (2008) Administration of IL-33 induces airway hyperresponsiveness and goblet cell hyperplasia in the lungs in the absence of adaptive immune system. Int Immunol 20:791–800

  28. Lee NA (2004) Defining a link with asthma in mice congenitally deficient in eosinphils. Science 305:1773–1776

  29. Marsland BJ, Kurrer M, Reissmann R, Harris NL, Kopf M (2008) Nippostrongylus brasiliensis infection leads to the development of emphysema associated with the induction of alternatively activated macrophages. Eur J Immunol 2008(38):479–488

  30. Matangkasombut P, Pichavant M, Dekruyff RH, Umetsu DT (2009) Natural killer T cells and the regulation of asthma. Mucosal Immunol 2:383–392

  31. McCarty TR, Turkeltaub JA, Hotez PJ (2014) Global progress towards eliminating gastrointestinal helminth infections. Curr Opin Gastroenterol 30:18–24

  32. Mehlotra RK, Hall LR, Haxhiu MA, Pearlman E (2001) Reciprocal immunomodulatory effects of gamma interferon and interleukin-4 on filaria-induced airway hyperresponsiveness. Infect Immun 69:1463–1468

  33. Moore PE, Calder M, Amrani Y, Panettieri RA Jr, Shore SA (2002) Effect of Th2 cytokines on human airway smooth muscle responses to LTD4. Am J Respir Crit Care Med 165:A116

  34. Nakae S, Morita H, Ohno T, Arae K, Matsumoto K, Saito H (2013) Role of interleukin-33 in innate-type immune cells in allergy. Allergol Int 62:13–20

  35. Negrão-Corrêa D, Souza DG, Pinho V, Barsante MM, Souza AL, Teixeira MM (2004) Platelet-activating factor receptor deficiency delays elimination of adult worms but reduces fecundity in Strongyloides venezuelensis-infected mice. Infect Immun 72:1135–1142

  36. Negrão-Corrêa D, Pinho V, Souza DG, Pereira AT, Fernandes A, Scheuermann K, Souza AL, Teixeira MM (2006) Expression of IL-4 receptor on non-bone marrow-derived cells is necessary for the timely elimination of Strongyloides venezuelensis in mice, but not for intestinal IL-4 production. Int J Parasitol 36:1185–1195

  37. Noben-Trauth N, Köhler G, Bürki K, Lederman B (1996) Efficient targeting of IL-4 gene in Balb/c embryonic stem cell line. Transgenic Res 5:487–491

  38. Oboki K, Ohno T, Kajiwara N (2010) IL-33 is a crucial amplifier of innate rather than acquired immunity. Proc Natl Acad Sci U S A 107:18581–18586

  39. Onah DN, Nawa Y (2000) Mucosal immunity against parasitic gastrointestinal nematodes. Korean J Parasitol 38:209–236

  40. Palmer LJ, Celedon JC, Weiss ST, Wang B, Fang Z, Xu X (2002) Ascaris lumbricoides infection is associated with increased risk of childhood asthma and atopy in rural China. Am J Respir Crit Care Med 65:1489–1493

  41. Patel N, Kreider T, Urban JF Jr, Gause WC (2009) Characterization of effector mechanisms at the host: parasite interface during the immune response to tissue-dwelling intestinal nematode parasites. Int J Parasitol 39:13–21

  42. Perkins C, Yanase N, Smulian G, Gildea L, Orekov T, Potter C, Brombacher F, Aronow B, Wills-Karp M, Finkelman FD (2011) Selective stimulation of IL-4 receptor on smooth muscle induces airway hyperresponsiveness in mice. J Exp Med 208:853–867

  43. Pinelli E, Brandes S, Dormans J, Gremmer E, Van Loveren H (2007) Infection with the roundworm Toxocara canis leads to exarcebation of experimental allergic airway inflammation. Clin Exp Allergy 38:649–658

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

  45. Puthiyakunnon S, Boddu S, Li Y, Zhou X, Wang C, Li J, Chen X (2014) Strongyloidiasis—an insight into its global prevalence and management. PLoS Negl Trop Dis 8(8):e3018

  46. Savenije OE, Mahachie John JM et al (2014) Association of IL33-IL-1 receptor-like 1 (IL1RL1) pathway polymorphisms with wheezing phenotypes and asthma in childhood. J Allergy Clin Immunol 134:170–177

  47. Shore SA (2004) Direct effects of Th2 cytokines on airway smooth muscle. Curr Opin Pharmacol 4:235–240

  48. Siddiqui AA, Berk SL (2001) Diagnosis of Strongyloides stercoralis infection. Clin Infect Dis 33:1040–1047, Review

  49. Silveira MR, Nunes KP, Cara DC, Souza DG, Corrêa A Jr, Teixeira MM, Negrão-Corrêa D (2002) Infection with Strongyloides venezuelensis induces transient airway eosinophilic inflammation, and increase in immunoglobulin E, and hyperresponsiveness in rats. Infect Immun 70:6263–6272

  50. Strath M, Warren DJ, Sanderson CJ (1985) Detection of eosinophils using an eosinophil peroxidase assay. Its use as an assay for eosinophil differentiation factors. J Immunol Methods 83:209–215

  51. Takamure A (1995) Migration route of Strongyloides venezuelensis in rodents. Int J Parasitol 25:907–911

  52. Teixeira MM, Williams TJ, Hellewell PG (1995) Mechanisms and pharmacological manipulation of eosinophil accumulation in vivo. Trends Pharmacol Sci 16:418–423

  53. Tomita M, Kobayashi T, Itoh H, Onitsuka T (2000) Goblet cell hyperplasia in the airway of Nippostrongylus brasiliensis-infected rats. Respiration 67:565–569

  54. Townsend MJ, Fallon PG, Matthews DJ, Jolin HE, McKenzie ANJ (2000) T1/ST2-deficient mice demonstrate the importance of T1/ST2 in developing primary T helper cell type 2 responses. J Exp Med 191:1069–1075

  55. Urban JF Jr, Madden KB, Svetić A, Cheever A, Trotta PP, Gause WC, Katona IM, Finkelman FD (1992) The importance of Th2 cytokines in protective immunity to nematodes. Immunol Rev 127:205–220

  56. Van Hove CL, Maes T, Cataldo DD, Guéders MM, Palmans E, Joos GF, Tournoy KG (2009) Comparison of acute inflammatory and chronic structural asthma-like responses between C57BL/6 and BALB/c mice. Int Arch Allergy Immunol 149:195–207

  57. Walsh MG (2011) Toxocara infection and diminished lung function in a nationally representative sample from the United States population. Int J Parasitol 41:243–247

  58. Walter DM, McIntire JJ, Berry G, McKenzie AN, Donaldson DD, DeKruyff RH, Umetsu DT (2001) Critical role for IL-13 in the development of allergen-induced airway hyperreactivity. J Immunol 167:4668–4675

  59. Wang Y, McCusker CT (2005) Interleukin IL-13-dependent bronchial hype- responsiveness following isolated upper-airway allergen challenge in a murine model of allergic rhinitis and asthma. Clin Exp Allergy 35:1104–1111

  60. Webb DC, Matthaei KI, Cai Y, McKenzie AN, Foster PS (2004) Polymorphisms in IL-4R alpha correlate with airways hyperreactivity, eosinophilia, and Ym protein expression in allergic IL-13-/- mice. J Immunol 172:1092–1098

  61. Wehrmann F, Lavelle JC, Collins CB, Tinega AN, Thurman JM, Burnham EL, Simonian PL (2016) γδ T cells protect against LPS-induced lung injury. J Leukoc Biol 99:373–386

  62. Wills-Karp M, Karp CL (2004) Eosinophils in asthma: remodeling a tangled tale. Science 305:1726–1729

  63. Wills-Karp M, Luyimbazi J, Xu X, Schofield B, Neben TY, Karp CL, Donaldson DD (1998) Interleukin-13: central mediator of allergic asthma. Science 282:2258–2261

  64. Wynn TA (2003) IL-13 effector functions. Annu Rev Immunol 21:425–456

  65. Yasuda K, Muto T, Kawagoe T, Matsumoto M, Sasaki Y, Matsushita K, Taki Y, Futatsugi-Yumikura S, Tsutsui H, Ishii KJ, Yoshimoto T, Akira S, Nakanishi K (2012) Contribution of IL-33-activated type II innate lymphoid cells to pulmonary eosinophilia in intestinal nematode-infected mice. Proc Natl Acad Sci U S A 109:3451–3456

  66. Yu C, Cantor AB, Yang H, Browne C, Wells RA, Fujiwara Y, Orkin SH (2002) Targeted deletion of a high-affinity GATA-binding site in the GATA-1 promoter leads to selective loss of the eosinophil lineage in vivo. J Exp Med 195:1387–1395

  67. Zhao A, McDermott J, Urban JF Jr, Gause W, Madden KB, Yeung KA, Morris SC, Finkelman FD, Shea-Donohue T (2003) Dependence of IL-4, IL-13, and nematode-induced alterations in murine small intestinal smooth muscle contractility on Stat-6 and enteric nerves. J Immunol 171:948–954

  68. Zhu Z, Homer RJ, Wang Z, Chen Q, Geba GP, Wang J, Zhang Y, Elias JA (1999) Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, sub epithelial fibrosis, physiologic abnormalities, and eotaxin production. J Clin Invest 103:779–788

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This study received financial support from the Fundação de Amparo a Pesquisas do Estado de Minas Gerais (FAPEMIG) and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES-Brazil, Basic Parasitology Program).

Authors’ contribution

Conceived of or designed the study: ESA, CAJP, MMT, and DNC

Performed parasitological and histopathological experiments: ESA, CAJP, JRL, MCR, JMPM, and DNC.

Optimized the methodology and performed AHR in infected animals: ESA, CAJP, ATMP, and MMT

Analyzed data: ESA and DNC

Wrote the manuscript: ESA, MMT, and DNC

The authors read and approved the final manuscript.

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Correspondence to Deborah Negrão-Corrêa.

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The authors declare no conflicts of interest.

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In memoriam of Ana Terezinha de Moura Pereira

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Araujo, E.S., de Jesus Pereira, C.A., de Moura Pereira, A.T. et al. The role of IL-33/ST2, IL-4, and eosinophils on the airway hyperresponsiveness induced by Strongyloides venezuelensis in BALB/c mice. Parasitol Res 115, 3107–3117 (2016). https://doi.org/10.1007/s00436-016-5066-6

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  • Strongyloides venezuelensis
  • Airway hyperresponsiveness
  • IL-33/ST2 pathway
  • IL-4 and eosinophils