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Critical link between TRAIL and CCL20 for the activation of TH2 cells and the expression of allergic airway disease

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.

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Figure 1: TRAIL is increased in allergic mice and regulated by TH2 cells.
Figure 2: TRAIL deficiency abolishes AHR and reduces airway inflammation.
Figure 3: TRAIL deficiency impairs DC and T-cell homing, CCL20, TH2 cytokine release and STAT6 activation.
Figure 4: Silencing TRAIL by siRNA abolishes AHR and reduces inflammation and TH2 cytokine release.
Figure 5: TRAIL induces AHR, inflammation and cytokine release in an IL-13–dependent manner.
Figure 6: TRAIL is increased in sputum of individuals with asthma and induces CCL20 release from bronchial epithelial cells.

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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.).

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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.

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Correspondence to Joerg Mattes.

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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.

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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

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