Abstract
The role of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) in immune responses mediated by T-helper 2 (TH2) lymphocytes is unknown. Here we characterize the development of allergic airway disease in TRAIL-deficient (Tnfsf10−/−) mice and in mice exposed to short interfering RNA targeting TRAIL. We show that TRAIL is abundantly expressed in the airway epithelium of allergic mice and that inhibition of signaling impairs production of the chemokine CCL20 and homing of myeloid dendritic cells and T cells expressing CCR6 and CD4 to the airways. Attenuated homing limits TH2 cytokine release, inflammation, airway hyperreactivity and expression of the transcriptional activator STAT6. Activation of STAT6 by interleukin-13 restores airway hyperreactivity in Tnfsf10−/− mice. Recombinant TRAIL induces pathognomic features of asthma and stimulates the production of CCL20 in primary human bronchial epithelium cells. TRAIL is also increased in sputum of asthmatics. The function of TRAIL in the airway epithelium identifies this molecule as a target for the treatment of asthma.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Bousquet, J., Bousquet, P.J., Godard, P. & Daures, J.P. The public health implications of asthma. Bull. World Health Organ. 83, 548–554 (2005).
Wills-Karp, M. Immunological basis of antigen-induced airways hyperresponsiveness. Annu. Rev. Immunol. 17, 255–281 (1999).
Busse, W.W. Inflammation in asthma: the cornerstone of the disease and target of therapy. J. Allergy Clin. Immunol. 102, S17–S22 (1998).
Kay, A.B. Allergy and allergic diseases. First of two parts. N. Engl. J. Med. 344, 30–37 (2001).
Corry, D.B. et al. Interleukin 4, but not interleukin 5 or eosinophils, is required in a murine model of acute airway hyperreactivity. J. Exp. Med. 183, 109–117 (1996).
Foster, P.S., Hogan, S.P., Ramsay, A.J., Matthaei, K.I. & Young, I.G. Interleukin 5 deficiency abolishes eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model. J. Exp. Med. 183, 195–201 (1996).
Temann, U.A., Geba, G.P., Rankin, J.A. & Flavell, R.A. Expression of interleukin 9 in the lungs of transgenic mice causes airway inflammation, mast cell hyperplasia, and bronchial hyperresponsiveness. J. Exp. Med. 188, 1307–1320 (1998).
Wills-Karp, M. et al. Interleukin-13: central mediator of allergic asthma. Science 282, 2258–2261 (1998).
Grunig, G. et al. Requirement for IL-13 independently of IL-4 in experimental asthma. Science 282, 2261–2263 (1998).
Robinson, D.S. et al. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N. Engl. J. Med. 326, 298–304 (1992).
Bentley, A.M. et al. Increases in activated T lymphocytes, eosinophils, and cytokine mRNA expression for interleukin-5 and granulocyte/macrophage colony-stimulating factor in bronchial biopsies after allergen inhalation challenge in atopic asthmatics. Am. J. Respir. Cell Mol. Biol. 8, 35–42 (1993).
Kroegel, C., Julius, P., Matthys, H., Virchow, J.C. Jr. & Luttmann, W. Endobronchial secretion of interleukin-13 following local allergen challenge in atopic asthma: relationship to interleukin-4 and eosinophil counts. Eur. Respir. J. 9, 899–904 (1996).
Lambrecht, B.N., Salomon, B., Klatzmann, D. & Pauwels, R.A. Dendritic cells are required for the development of chronic eosinophilic airway inflammation in response to inhaled antigen in sensitized mice. J. Immunol. 160, 4090–4097 (1998).
Lambrecht, B.N. et al. Myeloid dendritic cells induce Th2 responses to inhaled antigen, leading to eosinophilic airway inflammation. J. Clin. Invest. 106, 551–559 (2000).
Lewkowich, I.P. et al. CD4+CD25+ T cells protect against experimentally induced asthma and alter pulmonary dendritic cell phenotype and function. J. Exp. Med. 202, 1549–1561 (2005).
Kohl, J. et al. A regulatory role for the C5a anaphylatoxin in type 2 immunity in asthma. J. Clin. Invest. 116, 783–796 (2006).
Lambrecht, B.N. & Hammad, H. Taking our breath away: dendritic cells in the pathogenesis of asthma. Nat. Rev. Immunol. 3, 994–1003 (2003).
Le Borgne, M. et al. Dendritic cells rapidly recruited into epithelial tissues via CCR6/CCL20 are responsible for CD8+ T cell crosspriming in vivo. Immunity 24, 191–201 (2006).
Thorley, A.J., Goldstraw, P., Young, A. & Tetley, T.D. Primary human alveolar type II epithelial cell CCL20 (macrophage inflammatory protein-3α)-induced dendritic cell migration. Am. J. Respir. Cell Mol. Biol. 32, 262–267 (2005).
Dieu-Nosjean, M.C. et al. Macrophage inflammatory protein 3α is expressed at inflamed epithelial surfaces and is the most potent chemokine known in attracting Langerhans cell precursors. J. Exp. Med. 192, 705–718 (2000).
Reibman, J., Hsu, Y., Chen, L.C., 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. 28, 648–654 (2003).
Zhang, Y. et al. Mobilization of dendritic cell precursors into the circulation by administration of MIP-1α in mice. J. Natl. Cancer Inst. 96, 201–209 (2004).
Wiley, S.R. et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 3, 673–682 (1995).
Locksley, R.M., Killeen, N. & Lenardo, M.J. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 104, 487–501 (2001).
Aggarwal, B.B., Shishodia, S., Ashikawa, K. & Bharti, A.C. The role of TNF and its family members in inflammation and cancer: lessons from gene deletion. Curr. Drug Targets Inflamm. Allergy 1, 327–341 (2002).
Robertson, N.M. et al. Differential expression of TRAIL and TRAIL receptors in allergic asthmatics following segmental antigen challenge: evidence for a role of TRAIL in eosinophil survival. J. Immunol. 169, 5986–5996 (2002).
Zhang, X.R. et al. Reciprocal expression of TRAIL and CD95L in Th1 and Th2 cells: role of apoptosis in T helper subset differentiation. Cell Death Differ. 10, 203–210 (2003).
Daigle, I. & Simon, H.U. Alternative functions for TRAIL receptors in eosinophils and neutrophils. Swiss Med. Wkly. 131, 231–237 (2001).
Takeda, K. et al. Critical role for tumor necrosis factor-related apoptosis-inducing ligand in immune surveillance against tumor development. J. Exp. Med. 195, 161–169 (2002).
Smyth, M.J. et al. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) contributes to interferon γ-dependent natural killer cell protection from tumor metastasis. J. Exp. Med. 193, 661–670 (2001).
Takeda, K. et al. Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells. Nat. Med. 7, 94–100 (2001).
Walczak, H. et al. Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat. Med. 5, 157–163 (1999).
Lamhamedi-Cherradi, S.E., Zheng, S.J., Maguschak, K.A., Peschon, J. & Chen, Y.H. Defective thymocyte apoptosis and accelerated autoimmune diseases in TRAIL−/− mice. Nat. Immunol. 4, 255–260 (2003).
Begue, B. et al. Implication of TNF-related apoptosis-inducing ligand in inflammatory intestinal epithelial lesions. Gastroenterology 130, 1962–1974 (2006).
Mattes, J. et al. IL-13 induces airways hyperreactivity independently of the IL-4Rα chain in the allergic lung. J. Immunol. 167, 1683–1692 (2001).
Kuperman, D.A. et al. Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma. Nat. Med. 8, 885–889 (2002).
van Rijt, L.S. et al. In vivo depletion of lung CD11c+ dendritic cells during allergen challenge abrogates the characteristic features of asthma. J. Exp. Med. 201, 981–991 (2005).
van Rijt, L.S. et al. Essential role of dendritic cell CD80/CD86 costimulation in the induction, but not reactivation, of TH2 effector responses in a mouse model of asthma. J. Allergy Clin. Immunol. 114, 166–173 (2004).
Akbari, O. et al. Antigen-specific regulatory T cells develop via the ICOS-ICOS ligand pathway and inhibit allergen-induced airway hyperreactivity. Nat. Med. 8, 1024–1032 (2002).
Lukacs, N.W., Prosser, D.M., Wiekowski, M., Lira, S.A. & Cook, D.N. Requirement for the chemokine receptor CCR6 in allergic pulmonary inflammation. J. Exp. Med. 194, 551–555 (2001).
Lundy, S.K. et al. Attenuation of allergen-induced responses in CCR6−/− mice is dependent upon altered pulmonary T lymphocyte activation. J. Immunol. 174, 2054–2060 (2005).
Mattes, J. et al. Intrinsic defect in T cell production of interleukin (IL)-13 in the absence of both IL-5 and eotaxin precludes the development of eosinophilia and airways hyperreactivity in experimental asthma. J. Exp. Med. 195, 1433–1444 (2002).
Taube, C. et al. The role of IL-13 in established allergic airway disease. J. Immunol. 169, 6482–6489 (2002).
Walter, D.M. et al. Critical role for IL-13 in the development of allergen-induced airway hyperreactivity. J. Immunol. 167, 4668–4675 (2001).
Venkayya, R. et al. The Th2 lymphocyte products IL-4 and IL-13 rapidly induce airway hyperresponsiveness through direct effects on resident airway cells. Am. J. Respir. Cell Mol. Biol. 26, 202–208 (2002).
Yuan, B., Latek, R., Hossbach, M., Tuschl, T. & Lewitter, F. siRNA Selection Server: an automated siRNA oligonucleotide prediction server. Nucleic Acids Res. 32, W130–W134 (2004).
Kayagaki, N. et al. Expression and function of TNF-related apoptosis-inducing ligand on murine activated NK cells. J. Immunol. 163, 1906–1913 (1999).
Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, November 1986. Am. Rev. Respir. Dis. 136, 225–244 (1987).
Mattes, J. et al. NO in exhaled air is correlated with markers of eosinophilic airway inflammation in corticosteroid-dependent childhood asthma. Eur. Respir. J. 13, 1391–1395 (1999).
Contoli, M. et al. Role of deficient type III interferon-λ production in asthma exacerbations. Nat. Med. 12, 1023–1026 (2006).
Acknowledgements
We thank H. Rosenberg and R. Kumar for comments on the manuscript; J. Peschon (AMGEN, USA) for Tnfsf10−/− mice; A.N. McKenzie (Cambridge, UK) for Il13−/− mice; and S. Driever, G. Korth, J.C. Simon and staff from the Animal Care Facility of the contributing institutes for technical assistance. This study was supported by the Landesstiftung Baden-Wuerttemberg, Forschungsprogramm 'Allergologie' (P-LS-AL/5 to J.M.), and in part by the Forschungskommission Universitaet Freiburg (J.M.), the Wissenschaftliche Gesellschaft Freiburg (J.M.), a National Health Medical Research Council (NH&MRC) Program Grant (J.M., K.I.M., P.S.F.), the Hunter Medical Research Institute (J.M., P.S.F.), a Jardine Lloyd Thompson Fellowship (J.M.) and an NH&MRC Program Grant and Research Fellowship (M.J.S.).
Author information
Authors and Affiliations
Contributions
M.W. and A.C. performed mouse experiments, analyzed and interpreted data, and generated figures. A.C., J.L.S., M.V.K., P.A.B.W., B.W. and P.G.G. performed and supervised human studies, analyzed and interpreted data, and contributed to manuscript discussion. N.H. performed and analyzed parts of the invasive AHR measurements. M.J.S. and K.I.M. backcrossed and bred mice, contributed to data discussion, and revised the manuscript. H.Y. generated the N2B2 clone and TRAIL 2PK-3 cells, purified TRAIL antibodies, contributed to data discussion, and revised the manuscript. P.S.F. supervised mouse studies, designed mouse experiments, analyzed and interpreted data, and edited the manuscript. J.M. coordinated, designed, supervised and performed mouse and human studies; generated figures; analyzed and interpreted data; and drafted and edited the manuscript.
Corresponding author
Ethics declarations
Competing interests
The University of Freiburg and the University of Newcastle (with which some of the authors are affiliated) have submitted patent applications related to the role of TRAIL in allergic airway disease.
Supplementary information
Supplementary Text and Figures
Supplementary Methods and Supplementary Figs. 1–7 (PDF 352 kb)
Rights and permissions
About this article
Cite this article
Weckmann, M., Collison, A., Simpson, J. et al. Critical link between TRAIL and CCL20 for the activation of TH2 cells and the expression of allergic airway disease. Nat Med 13, 1308–1315 (2007). https://doi.org/10.1038/nm1660
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nm1660
This article is cited by
-
Common and disorder-specific upregulation of the inflammatory markers TRAIL and CCL20 in depression and schizophrenia
Scientific Reports (2021)
-
TRAIL signals through the ubiquitin ligase MID1 to promote pulmonary fibrosis
BMC Pulmonary Medicine (2019)
-
The Absence of Interferon-β Promotor Stimulator-1 (IPS-1) Predisposes to Bronchiolitis and Asthma-like Pathology in Response to Pneumoviral Infection in Mice
Scientific Reports (2017)
-
A pathogenic role for tumor necrosis factor-related apoptosis-inducing ligand in chronic obstructive pulmonary disease
Mucosal Immunology (2016)
-
Small interfering RNA against CD86 during allergen challenge blocks experimental allergic asthma
Respiratory Research (2014)