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Table of Contents
Vol. 3, No. 2, 2011
Issue release date: February 2011
Section title: Research Article
Free Access
J Innate Immun 2011;3:167–179
(DOI:10.1159/000320718)

Early Immunological Response to German Cockroach Frass Exposure Induces a Th2/Th17 Environment

Page K.a, c · Zhou P.a · Ledford J.R.a · Day S.B.a · Lutfi R.a · Dienger K.b · Lewkowich I.P.b
Divisions of aCritical Care Medicine and bImmunobiology, Cincinnati Children’s Hospital Medical Center and Cincinnati Children’s Research Foundation, and cDepartment of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA
email Corresponding Author

Abstract

Cockroach exposure is a major risk factor for the development of asthma; however, the early immune events induced by cockroach leading to the Th2 response are not fully understood. Exposure of naïve mice to German cockroach (GC) feces (frass) was sufficient to induce dendritic cell (DC) recruiting and activating chemokines C-C motif ligand 20, granulocyte macrophage colony-stimulating factor, granulocyte colony-stimulating factor and macrophage inflammatory protein-1α into the airways. This corresponded with an increase in myeloid DCs (mDCs) in the airways as well as increased expression of CD80 and CD86 on the mDCs. Plasmacytoid DCs in the lung were unchanged. Levels of IL-5, IL-17A and IL-6 cytokines in whole lung cultures were significantly increased 18 h following GC frass exposure demonstrating the early development of a mixed Th2/Th17 response. In addition, GC frass stimulated the production of IL-23, IL-6 and IL-12p70 from bone marrow-derived mDCs. Adoptive transfer of GC frass-pulsed mDCs induced airway reactivity, airway inflammation as well as eosinophilia and induced a strong Th2/Th17 response in the lung. MyD88-deficient bone marrow-derived mDCs did not respond to GC frass treatment, suggesting a functional Toll-like receptor pathway was important to induce the Th2/Th17 response. Together, our data show that GC frass activated the innate immune response to augment DC recruitment and activation of mDCs which promoted robust T cell-skewing cytokines and ultimately drive the development of airway inflammation.

© 2010 S. Karger AG, Basel


  

Key Words

  • Chemokines
  • Cytokines
  • Immune response
  • Pathogen associated-molecular patterns
  • Toll-like receptor
  • Dendritic cell
  • Airway inflammation
  • Cockroach

References

  1. Pollart SM, Smith TF, Morris EC, Gelber LE, Platts-Mills TA, Chapman MD: Environmental exposure to cockroach allergens: analysis with monoclonal antibody-based enzyme immunoassays. J Allergy Clin Immunol 1991;87:505–510.
  2. Gelber LE, Seltzer LH, Bouzoukis JK, Pollart SM, Chapman MD, Platts-Mills TA: Sensitization and exposure to indoor allergens as risk factors for asthma patients presenting to hospital. Am Rev Respir Dis 1993;147:573–587.
  3. Rosenstreich DL, Eggleston P, Kattan M, Baker D, Slavin RG, Gergen P, Mitchell H, McNiff-Mortimer K, Lynn H, Ownby D, et al: The role of cockroach allergy and exposure to cockroach allergen is causing morbidity among inner city children with asthma. New Engl J Med 1997;336:1356–1363.
  4. Sporik R, Squillace SP, Ingram JM, Rakes G, Honsinger RW, Platts-Mills TA: Mite, cat, and cockroach exposure, allergen sensitisation, and asthma in children: a case-control study of three schools. Thorax 1999;54:675–680.
  5. Page K, Lierl K, Herman N, Wills-Karp M: Differences in susceptibility to German cockroach frass and its associated proteases in induced allergic inflammation in mice. Respir Res 2007;8:91.
  6. Page K, Lierl KM, Hughes VS, Zhou P, Ledford JR, Wills-Karp M: TLR2-mediated activation of neutrophils in response to German cockroach frass. J Immunol 2008;180:6317–6324.
  7. Day SB, Zhou P, Ledford JR, Page K: German cockroach frass proteases modulate the innate immune response via activation of protease-activated receptor-2. J Innate Immun 2010;2:495–504.
  8. Holt PG, Schon-Hegrad MA, Oliver J, Holt BJ, McMenamin PG: A contiguous network of dendritic antigen-presenting cells within the respiratory epithelium. Inter Arch Allergy Appl Immunol 1990;91:155–159.
  9. Charbonnier AS, Kohrgruber N, Kriehuber E, Stingl G, Rot A, Maurer D: Macrophage inflammatory protein 3 α is involved in the constitutive trafficking of epidermal Langerhans cells. J Exp Med 1999;190:1755–1768.
  10. Weckmann M, Collison A, Simpson JL, Kopp MV, Wark PA, Smyth MJ, Yagita H, Matthaei KI, Hansbro N, Whitehead B, et al: Critical link between TRAIL and CCL20 for the activation of TH2 cells and the expression of allergic airway disease. Nat Med 2007;13:1308–1315.
  11. Jahnsen FL, Moloney ED, Hogan T, Upham JW, Burke CM, Holt PG: Rapid dendritic cell recruitment to the bronchial mucosa of patients with atopic asthma in response to local allergen challenge. Thorax 2001;56:823–826.
  12. Cates EC, Fattouh R, Wattie J, Inman MD, Goncharova S, Coyle AJ, Gutierrez-Ramos JC, Jordana M: Intranasal exposure of mice to house dust mite elicits allergic airway inflammation via a GM-CSF-mediated mechanism. J Immunol 2004;173:6384–6392.
  13. Romani N, Gruner S, Brang D, Kampgen E, Lenz A, Trockenbacher B, Konwalinka G, Fritsch PO, Steinman RM, Schuler G: Proliferating dendritic cell progenitors in human blood. J Exp Med 1994;180:83–93.
  14. Cella M, Scheidegger D, Palmer-Lehmann K, Lane P, Lanzavecchia A, Alber G: Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation. J Exp Med 1996;184:747–752.
  15. Kohrgruber N, Halanek N, Gröger M, Winter D, Rappersberger K, Schmitt-Egenolf M, Stingl G, Maurer D: Survival, maturation, and function of CD11c– and CD11c+ peripheral blood dendritic cells are differentially regulated by cytokines. J Immunol 1999;163:3250–3259.
  16. Cella M, Jarrossay D, Facchetti F, Alebardi O, Nakajima H, Lanzavecchia A, Colonna M: Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon. Nat Med 1999;5:919–923.
  17. Kool M, van Nimwegen M, Willart MA, Muskens F, Boon L, Smit JJ, Coyle A, Clausen BE, Hoogsteden HC, Lambrecht BN, et al: An anti-inflammatory role for plasmacytoid dendritic cells in allergic airway inflammation. J Immunol 2009;183:1074–1082.
  18. Lewkowich IP, Lajoie S, Clark JR, Herman NS, Spoles AA, Wills-Karp M: Allergen uptake, activation, and IL-23 production by pulmonary myeloid DCs drives ariway hyperresponsiveness in asthma-susceptible mice. PLoS One 2008;3:e3879.
  19. Rincón M, Anguita J, Nakamura T, Fikrig E, Flavell RA: Interleukin (IL)-6 directs the differentiation of IL-4-producing CD4+ T cells. J Exp Med 1997;185:461–469.
  20. Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B: TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 2006;24:179–189.
  21. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK: Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006;441:235–238.
  22. Macatonia SE, Hosken NA, Litton M, Vieira P, Hsieh CS, Culpepper JA, Wysocka M, Trinchieri G, Murphy KM, O’Garra A: Dendritic cells produce IL-12 and direct the development of Th1 cells from naive CD4+ T cells. J Immunol 1995;154:5071–5079.
  23. Barczyk A, Pierzchala W, Sozañska E: Interleukin-17 in sputum correlates with airway hyperresponsiveness to methacholine. Respir Med 2003;97:726–733.
  24. Chakir J, Shannon J, Molet S, Fukakusa M, Elias JA, Laviolette M, Boulet LP, Hamid Q: Airway remodeling-associated mediators in moderate to severe asthma: effect of steroids on TNF-β, IL-11, IL-17 and type I and type III collagen expression. J Allergy Clin Immunol 2003;111:1293–1298.
  25. Takeuchi O, Hoshino K, Akira S: TLR2-deficient and MyD88-deficient mice are highly susceptible to Staphylococcus aureus infection. J Immunol 2000;165:5392–5396.
  26. Walters DM, Breysse PN, Wills-Karp M: Ambient urban Baltimore particulate-induced airway hyperresponsiveness and inflammation in mice. Am J Respir Crit Care Med 2001;164:1438–1443.
  27. Wills-Karp M, Luyimbazi J, Xu X, Schofield B, Neben TY, Karp CL, Donaldson DD: Interleukin-13: central mediator of allergic asthma. Science 1988;282:2258–2261.
  28. Ewart S, Levitt R, Mitzner W: Respiratory system mechanisms in mice measured by end-inflation occlusion. J Appl Physiol 1995;79:560–566.
  29. Reibman J, Hsu Y, Chen LC, Bleck B, Gordon T: Airway epithelial cells release MIP-3α/CCL20 in response to cytokines and ambient particulate matter. Am J Respir Cell Mol Biol 2003;28:648–654.
  30. Nathan AT, Peterson EA, Chakir J, Wills-Karp M: Innate immune responses of airway epithelium to house dust mite are mediated through b-glucan-dependent pathways. J Allergy Clin Immunol 2009;123:612–618.
  31. King C, Brennan S, Thompson PJ, Stewart GA: Dust mite proteolytic allergens induce cytokine release from cultured airway epithelium. J Immunol 1998;161:3645–3651.
  32. Osterlund C, Grönlund H, Polovic N, Sundström S, Gafvelin G, Bucht A: The non-proteolytic house dust mite allergen Der p 2 induce NF-ĸB and MAPK dependent activation of bronchial epithelial cells. Clin Exp Allergy 2009;39:1199–1208.
  33. Li L, Huang L, Vergis AL, Ye H, Bajwa A, Narayan V, Streiter RM, Rosin Dl, Okusa MD: IL-17 produced by neutrophils regulates IFN-ĸ-mediated neutrophil migration in mouse kidney ischemia-reperfusion injury. J Clin Invest 2010;120:331–342.
  34. Wilson RH, Whitehead GS, Nakano H, Free ME, Kolls JK, Cook DN: Allergic sensitization through the airway primes Th17-dependent neutrophilia and airway hyperresponsiveness. Am J Respir Crit Care Med 2009;180:720–730.
  35. Nakae S, Komiyama Y, Nambu A, Sudo K, Iwase M, Homma I, Sekikawa K, Asano M, Iwakura Y: Antigen-specific T cell sensitization is impaired in IL-17-deficient mice, causing suppression of allergic cellular and humoral responses. Immunity 2002;17:375–387.
  36. Oda N, Canelos PB, Essayan DM, Plunkett BA, Myers AC, Huang SK: Interleukin-17F induces pulmonary neutrophilia and amplifies antigen-induced allergic response. Am J Respir Crit Care Med 2005;171:12–18.
  37. He R, Kim HY, Yoon J, Oyoshi MK, MacGinnitie A, Goya S, Freyschmidt EJ, Bryce P, McKenzie AN, Umetsu DT, et al: Exaggerated IL-17 response to epicutaneous sensitization mediates airway inflammation in the absence of IL-4 and IL-13. J Allergy Clin Immunol 2009;124:761–770.
  38. Al-Ramli W, Préfontaine D, Chouiali F, Martin JG, Olivenstein R, Lemière C, Hamid Q: T(H)17-associated cytokines (IL-17A and IL-17F) in severe asthma. J Allergy Clin Immunol 2009;123:1185–1187.
  39. Page K, Ledford JR, Zhou P, Wills-Karp M: Mucosal sensitization to German cockroach involves protease-activated receptor-2. Respir Res 2010;11:62.
  40. Dharajiya N, Vaidya S, Sinha M, Luxon B, Boldogh I, Sur S: Allergen challenge induces IFN-γ dependent GTPases in the lungs as part of a Th1 transcriptome response in a murine model of allergic asthma. PLoS One 2009;4:e8172.
  41. Esashi E, Wang YH, Perng O, Qin XF, Liu YJ, Watowich SS: The signal transducer STAT5 inhibits plasmacytoid dendritic cell development by suppressing transcription factor IRF8. Immunity 2008;28:509–520.
  42. Lambrecht BN, DeVeerman M, Coyle AJ, Gutierrez-Ramos JC, Theilemans K, Pauwels RA: Myeloid dendritic cells induce Th2 responses to inhaled antigen, leading to eosinophilic airway inflammation. J Clin Invest 2000;106:551–559.
  43. Denning TL, Wang YC, Patel SR, Williams IR, Pulendran B: Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nature Immunol 2007;8:1086–1094.
  44. de Heer HJ, Hammad H, Soullié T, Hijdra D, Vos N, Willart MA, Hoogsteden HC, Lambrecht BN: Essential role of lung plasmacytoid dendritic cells in preventing asthmatic reactions to harmless inhaled antigen. J Exp Med 2004;200:89–98.
  45. Ito T, Amakawa R, Inaba M, Hori T, Ota M, Nakamura K, Takebayashi M, Miyaji M, Yoshimura T, Inaba K, et al: Plasmacytoid dendritic cells regulate Th cell responses through OX40 ligand and type I IFNs. J Immunol 2004;172:4253–4259.
  46. Matsuda H, Suda T, Hashizume H, Yokomura K, Asada K, Suzuki K, Chida K, Nakamura H: Alteration of balance between myeloid dendritic cells and plasmacytoid dendritic cells in peripheral blood of patients with asthma. Am J Respir Crit Care Med 2002;166:1050–1054.
  47. Bratke K, Lommatzsch M, Julius P, Kuepper M, Kleine HD, Luttmann W, Christian Virchow J: Dendritic cell subsets in human bronchoalveolar lavage fluid after segmental allergen challenge. Thorax 2007;62:168–175.

  

Author Contacts

Dr. Kristen Page
Division of Critical Care Medicine
Cincinnati Children’s Hospital Medical Center
3333 Burnet Avenue, ML 7006, Cincinnati, OH 45229 (USA)
Tel. +1 513 636 3079, Fax +1 513 636 4267, E-Mail kristen.page@cchmc.org

  

Article Information

Received: August 13, 2010
Accepted after revision: August 27, 2010
Published online: November 5, 2010
Number of Print Pages : 13
Number of Figures : 8, Number of Tables : 2, Number of References : 47

  

Publication Details

Journal of Innate Immunity

Vol. 3, No. 2, Year 2011 (Cover Date: February 2011)

Journal Editor: Herwald H. (Lund), Egesten A. (Lund)
ISSN: 1662-811X (Print), eISSN: 1662-8128 (Online)

For additional information: http://www.karger.com/JIN


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Cockroach exposure is a major risk factor for the development of asthma; however, the early immune events induced by cockroach leading to the Th2 response are not fully understood. Exposure of naïve mice to German cockroach (GC) feces (frass) was sufficient to induce dendritic cell (DC) recruiting and activating chemokines C-C motif ligand 20, granulocyte macrophage colony-stimulating factor, granulocyte colony-stimulating factor and macrophage inflammatory protein-1α into the airways. This corresponded with an increase in myeloid DCs (mDCs) in the airways as well as increased expression of CD80 and CD86 on the mDCs. Plasmacytoid DCs in the lung were unchanged. Levels of IL-5, IL-17A and IL-6 cytokines in whole lung cultures were significantly increased 18 h following GC frass exposure demonstrating the early development of a mixed Th2/Th17 response. In addition, GC frass stimulated the production of IL-23, IL-6 and IL-12p70 from bone marrow-derived mDCs. Adoptive transfer of GC frass-pulsed mDCs induced airway reactivity, airway inflammation as well as eosinophilia and induced a strong Th2/Th17 response in the lung. MyD88-deficient bone marrow-derived mDCs did not respond to GC frass treatment, suggesting a functional Toll-like receptor pathway was important to induce the Th2/Th17 response. Together, our data show that GC frass activated the innate immune response to augment DC recruitment and activation of mDCs which promoted robust T cell-skewing cytokines and ultimately drive the development of airway inflammation.

© 2010 S. Karger AG, Basel


  

Author Contacts

Dr. Kristen Page
Division of Critical Care Medicine
Cincinnati Children’s Hospital Medical Center
3333 Burnet Avenue, ML 7006, Cincinnati, OH 45229 (USA)
Tel. +1 513 636 3079, Fax +1 513 636 4267, E-Mail kristen.page@cchmc.org

  

Article Information

Received: August 13, 2010
Accepted after revision: August 27, 2010
Published online: November 5, 2010
Number of Print Pages : 13
Number of Figures : 8, Number of Tables : 2, Number of References : 47

  

Publication Details

Journal of Innate Immunity

Vol. 3, No. 2, Year 2011 (Cover Date: February 2011)

Journal Editor: Herwald H. (Lund), Egesten A. (Lund)
ISSN: 1662-811X (Print), eISSN: 1662-8128 (Online)

For additional information: http://www.karger.com/JIN


Article / Publication Details

First-Page Preview
Abstract of Research Article

Received: 8/13/2010
Accepted: 8/27/2010
Published online: 11/5/2010
Issue release date: February 2011

Number of Print Pages: 13
Number of Figures: 8
Number of Tables: 2

ISSN: 1662-811X (Print)
eISSN: 1662-8128 (Online)

For additional information: http://www.karger.com/JIN


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Pollart SM, Smith TF, Morris EC, Gelber LE, Platts-Mills TA, Chapman MD: Environmental exposure to cockroach allergens: analysis with monoclonal antibody-based enzyme immunoassays. J Allergy Clin Immunol 1991;87:505–510.
  2. Gelber LE, Seltzer LH, Bouzoukis JK, Pollart SM, Chapman MD, Platts-Mills TA: Sensitization and exposure to indoor allergens as risk factors for asthma patients presenting to hospital. Am Rev Respir Dis 1993;147:573–587.
  3. Rosenstreich DL, Eggleston P, Kattan M, Baker D, Slavin RG, Gergen P, Mitchell H, McNiff-Mortimer K, Lynn H, Ownby D, et al: The role of cockroach allergy and exposure to cockroach allergen is causing morbidity among inner city children with asthma. New Engl J Med 1997;336:1356–1363.
  4. Sporik R, Squillace SP, Ingram JM, Rakes G, Honsinger RW, Platts-Mills TA: Mite, cat, and cockroach exposure, allergen sensitisation, and asthma in children: a case-control study of three schools. Thorax 1999;54:675–680.
  5. Page K, Lierl K, Herman N, Wills-Karp M: Differences in susceptibility to German cockroach frass and its associated proteases in induced allergic inflammation in mice. Respir Res 2007;8:91.
  6. Page K, Lierl KM, Hughes VS, Zhou P, Ledford JR, Wills-Karp M: TLR2-mediated activation of neutrophils in response to German cockroach frass. J Immunol 2008;180:6317–6324.
  7. Day SB, Zhou P, Ledford JR, Page K: German cockroach frass proteases modulate the innate immune response via activation of protease-activated receptor-2. J Innate Immun 2010;2:495–504.
  8. Holt PG, Schon-Hegrad MA, Oliver J, Holt BJ, McMenamin PG: A contiguous network of dendritic antigen-presenting cells within the respiratory epithelium. Inter Arch Allergy Appl Immunol 1990;91:155–159.
  9. Charbonnier AS, Kohrgruber N, Kriehuber E, Stingl G, Rot A, Maurer D: Macrophage inflammatory protein 3 α is involved in the constitutive trafficking of epidermal Langerhans cells. J Exp Med 1999;190:1755–1768.
  10. Weckmann M, Collison A, Simpson JL, Kopp MV, Wark PA, Smyth MJ, Yagita H, Matthaei KI, Hansbro N, Whitehead B, et al: Critical link between TRAIL and CCL20 for the activation of TH2 cells and the expression of allergic airway disease. Nat Med 2007;13:1308–1315.
  11. Jahnsen FL, Moloney ED, Hogan T, Upham JW, Burke CM, Holt PG: Rapid dendritic cell recruitment to the bronchial mucosa of patients with atopic asthma in response to local allergen challenge. Thorax 2001;56:823–826.
  12. Cates EC, Fattouh R, Wattie J, Inman MD, Goncharova S, Coyle AJ, Gutierrez-Ramos JC, Jordana M: Intranasal exposure of mice to house dust mite elicits allergic airway inflammation via a GM-CSF-mediated mechanism. J Immunol 2004;173:6384–6392.
  13. Romani N, Gruner S, Brang D, Kampgen E, Lenz A, Trockenbacher B, Konwalinka G, Fritsch PO, Steinman RM, Schuler G: Proliferating dendritic cell progenitors in human blood. J Exp Med 1994;180:83–93.
  14. Cella M, Scheidegger D, Palmer-Lehmann K, Lane P, Lanzavecchia A, Alber G: Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation. J Exp Med 1996;184:747–752.
  15. Kohrgruber N, Halanek N, Gröger M, Winter D, Rappersberger K, Schmitt-Egenolf M, Stingl G, Maurer D: Survival, maturation, and function of CD11c– and CD11c+ peripheral blood dendritic cells are differentially regulated by cytokines. J Immunol 1999;163:3250–3259.
  16. Cella M, Jarrossay D, Facchetti F, Alebardi O, Nakajima H, Lanzavecchia A, Colonna M: Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon. Nat Med 1999;5:919–923.
  17. Kool M, van Nimwegen M, Willart MA, Muskens F, Boon L, Smit JJ, Coyle A, Clausen BE, Hoogsteden HC, Lambrecht BN, et al: An anti-inflammatory role for plasmacytoid dendritic cells in allergic airway inflammation. J Immunol 2009;183:1074–1082.
  18. Lewkowich IP, Lajoie S, Clark JR, Herman NS, Spoles AA, Wills-Karp M: Allergen uptake, activation, and IL-23 production by pulmonary myeloid DCs drives ariway hyperresponsiveness in asthma-susceptible mice. PLoS One 2008;3:e3879.
  19. Rincón M, Anguita J, Nakamura T, Fikrig E, Flavell RA: Interleukin (IL)-6 directs the differentiation of IL-4-producing CD4+ T cells. J Exp Med 1997;185:461–469.
  20. Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B: TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 2006;24:179–189.
  21. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK: Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006;441:235–238.
  22. Macatonia SE, Hosken NA, Litton M, Vieira P, Hsieh CS, Culpepper JA, Wysocka M, Trinchieri G, Murphy KM, O’Garra A: Dendritic cells produce IL-12 and direct the development of Th1 cells from naive CD4+ T cells. J Immunol 1995;154:5071–5079.
  23. Barczyk A, Pierzchala W, Sozañska E: Interleukin-17 in sputum correlates with airway hyperresponsiveness to methacholine. Respir Med 2003;97:726–733.
  24. Chakir J, Shannon J, Molet S, Fukakusa M, Elias JA, Laviolette M, Boulet LP, Hamid Q: Airway remodeling-associated mediators in moderate to severe asthma: effect of steroids on TNF-β, IL-11, IL-17 and type I and type III collagen expression. J Allergy Clin Immunol 2003;111:1293–1298.
  25. Takeuchi O, Hoshino K, Akira S: TLR2-deficient and MyD88-deficient mice are highly susceptible to Staphylococcus aureus infection. J Immunol 2000;165:5392–5396.
  26. Walters DM, Breysse PN, Wills-Karp M: Ambient urban Baltimore particulate-induced airway hyperresponsiveness and inflammation in mice. Am J Respir Crit Care Med 2001;164:1438–1443.
  27. Wills-Karp M, Luyimbazi J, Xu X, Schofield B, Neben TY, Karp CL, Donaldson DD: Interleukin-13: central mediator of allergic asthma. Science 1988;282:2258–2261.
  28. Ewart S, Levitt R, Mitzner W: Respiratory system mechanisms in mice measured by end-inflation occlusion. J Appl Physiol 1995;79:560–566.
  29. Reibman J, Hsu Y, Chen LC, Bleck B, Gordon T: Airway epithelial cells release MIP-3α/CCL20 in response to cytokines and ambient particulate matter. Am J Respir Cell Mol Biol 2003;28:648–654.
  30. Nathan AT, Peterson EA, Chakir J, Wills-Karp M: Innate immune responses of airway epithelium to house dust mite are mediated through b-glucan-dependent pathways. J Allergy Clin Immunol 2009;123:612–618.
  31. King C, Brennan S, Thompson PJ, Stewart GA: Dust mite proteolytic allergens induce cytokine release from cultured airway epithelium. J Immunol 1998;161:3645–3651.
  32. Osterlund C, Grönlund H, Polovic N, Sundström S, Gafvelin G, Bucht A: The non-proteolytic house dust mite allergen Der p 2 induce NF-ĸB and MAPK dependent activation of bronchial epithelial cells. Clin Exp Allergy 2009;39:1199–1208.
  33. Li L, Huang L, Vergis AL, Ye H, Bajwa A, Narayan V, Streiter RM, Rosin Dl, Okusa MD: IL-17 produced by neutrophils regulates IFN-ĸ-mediated neutrophil migration in mouse kidney ischemia-reperfusion injury. J Clin Invest 2010;120:331–342.
  34. Wilson RH, Whitehead GS, Nakano H, Free ME, Kolls JK, Cook DN: Allergic sensitization through the airway primes Th17-dependent neutrophilia and airway hyperresponsiveness. Am J Respir Crit Care Med 2009;180:720–730.
  35. Nakae S, Komiyama Y, Nambu A, Sudo K, Iwase M, Homma I, Sekikawa K, Asano M, Iwakura Y: Antigen-specific T cell sensitization is impaired in IL-17-deficient mice, causing suppression of allergic cellular and humoral responses. Immunity 2002;17:375–387.
  36. Oda N, Canelos PB, Essayan DM, Plunkett BA, Myers AC, Huang SK: Interleukin-17F induces pulmonary neutrophilia and amplifies antigen-induced allergic response. Am J Respir Crit Care Med 2005;171:12–18.
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