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Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice

Abstract

The cytokine thymic stromal lymphopoietin (TSLP) has been linked to human allergic inflammatory diseases. We show here that TSLP expression was increased in the lungs of mice with antigen-induced asthma, whereas TSLP receptor–deficient mice had considerably attenuated disease. Lung-specific expression of a Tslp transgene induced airway inflammation and hyperreactivity characterized by T helper type 2 cytokines and increased immunoglobulin E. The lungs of Tslp-transgenic mice showed massive infiltration of leukocytes, goblet cell hyperplasia and subepithelial fibrosis. TSLP was capable of activating bone marrow–derived dendritic cells to upregulate costimulatory molecules and produce the T helper type 2 cell–attracting chemokine CCL17. These findings suggest that TSLP is an important factor necessary and sufficient for the initiation of allergic airway inflammation.

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Figure 1: Upregulation of Tslp in the lungs of mice with OVA-induced airway inflammation.
Figure 2: TSLP receptor knockout reduces airway inflammation and goblet cell hyperplasia in OVA-induced mouse asthma.
Figure 3: BAL fluid of SPC-Tslp mice has an eosinophilic infiltrate.
Figure 4: SPC-Tslp-transgenic mice have TH2-biased inflammation.
Figure 5: Lung-infiltrating CD4+ T cells upregulate CCR4 while downregulating CD62L.
Figure 6: Lungs from SPC-Tslp mice have inflammatory infiltrates and show signs of airway remodeling.
Figure 7: Airway responsiveness.
Figure 8: Activation of BMDCs by recombinant mouse TSLP.

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References

  1. Umetsu, D.T., McIntire, J.J., Akbari, O., Macaubas, C. & DeKruyff, R.H. Asthma: an epidemic of dysregulated immunity. Nat. Immunol. 3, 715–720 (2002).

    Article  CAS  Google Scholar 

  2. Elias, J.A., Zhu, Z., Chupp, G. & Homer, R.J. Airway remodeling in asthma. J. Clin. Invest. 104, 1001–1006 (1999).

    Article  CAS  Google Scholar 

  3. Jeffery, P.K. Remodeling in asthma and chronic obstructive lung disease. Am. J. Respir. Crit. Care Med. 164, S28–S38 (2001).

    Article  CAS  Google Scholar 

  4. Burrows, B., Martinez, F.D., Halonen, M., Barbee, R.A. & Cline, M.G. Association of asthma with serum IgE levels and skin-test reactivity to allergens. N. Engl. J. Med. 320, 271–277 (1989).

    Article  CAS  Google Scholar 

  5. Coyle, A.J. et al. Interleukin-4 is required for the induction of lung TH2 mucosal immunity. Am. J. Respir. Cell Mol. Biol. 13, 54–59 (1995).

    Article  CAS  Google Scholar 

  6. Hogan, S.P. & Foster, P.S. Cellular and molecular mechanisms involved in the regulation of eosinophil trafficking in vivo. Med. Res. Rev. 16, 407–432 (1996).

    Article  CAS  Google Scholar 

  7. Cohn, L. et al. TH2-induced airway mucus production is dependent on IL-4Rα, but not on eosinophils. J. Immunol. 162, 6178–6183 (1999).

    CAS  Google Scholar 

  8. Townsend, J.M. et al. IL-9-deficient mice establish fundamental roles for IL-9 in pulmonary mastocytosis and goblet cell hyperplasia but not T cell development. Immunity 13, 573–583 (2000).

    Article  CAS  Google Scholar 

  9. Temann, U.A., Ray, P. & Flavell, R.A. Pulmonary overexpression of IL-9 induces TH2 cytokine expression, leading to immune pathology. J. Clin. Invest. 109, 29–39 (2002).

    Article  CAS  Google Scholar 

  10. Friend, S.L. et al. A thymic stromal cell line supports in vitro development of surface IgM+ B cells and produces a novel growth factor affecting B and T lineage cells. Exp. Hematol. 22, 321–328 (1994).

    CAS  Google Scholar 

  11. Ray, R.J., Furlonger, C., Williams, D.E. & Paige, C.J. Characterization of thymic stromal-derived lymphopoietin (TSLP) in murine B cell development in vitro. Eur. J. Immunol. 26, 10–16 (1996).

    Article  CAS  Google Scholar 

  12. Taneda, S. et al. Cryoglobulinemic glomerulonephritis in thymic stromal lymphopoietin transgenic mice. Am. J. Pathol. 159, 2355–2369 (2001).

    Article  CAS  Google Scholar 

  13. Soumelis, V. et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat. Immunol. 3, 673–680 (2002).

    Article  CAS  Google Scholar 

  14. Sugawara, N. et al. TARC in allergic disease. Allergy 57, 180–181 (2002).

    Article  CAS  Google Scholar 

  15. Sims, J.E. et al. Molecular cloning and biological characterization of a novel murine lymphoid growth factor. J. Exp. Med. 192, 671–680 (2000).

    Article  CAS  Google Scholar 

  16. Quentmeier, H. et al. Cloning of human thymic stromal lymphopoietin (TSLP) and signaling mechanisms leading to proliferation. Leukemia 15, 1286–1292 (2001).

    Article  CAS  Google Scholar 

  17. Osborn, M.J. et al. Overexpression of murine TSLP impairs lymphopoiesis and myelopoiesis. Blood 103, 843–851 (2004).

    Article  CAS  Google Scholar 

  18. Corry, D.B. & Kheradmand, F. Induction and regulation of the IgE response. Nature 402, B18–B23 (1999).

    Article  CAS  Google Scholar 

  19. Kim, C.H. et al. Rules of chemokine receptor association with T cell polarization in vivo. J. Clin. Invest. 108, 1331–1339 (2001).

    Article  CAS  Google Scholar 

  20. Campbell, J.J. et al. Expression of chemokine receptors by lung T cells from normal and asthmatic subjects. J. Immunol. 166, 2842–2848 (2001).

    Article  CAS  Google Scholar 

  21. Kay, A.B. Allergy and allergic diseases. First of two parts. N. Engl. J. Med. 344, 30–37 (2001).

    Article  CAS  Google Scholar 

  22. Walker, C. et al. Allergic and nonallergic asthmatics have distinct patterns of T-cell activation and cytokine production in peripheral blood and bronchoalveolar lavage. Am. Rev. Respir. Dis. 146, 109–115 (1992).

    Article  CAS  Google Scholar 

  23. Riffo-Vasquez, Y. & Spina, D. Role of cytokines and chemokines in bronchial hyperresponsiveness and airway inflammation. Pharmacol. Ther. 94, 185–211 (2002).

    Article  CAS  Google Scholar 

  24. Al-Shami, A. et al. A role for thymic stromal lymphopoietin in CD4+ T cell development. J. Exp. Med. 200, 159–168 (2004).

    Article  CAS  Google Scholar 

  25. Panina-Bordignon, P. et al. The C–C chemokine receptors CCR4 and CCR8 identify airway T cells of allergen-challenged atopic asthmatics. J. Clin. Invest. 107, 1357–1364 (2001).

    Article  CAS  Google Scholar 

  26. Bochner, B.S., Hudson, S.A., Xiao, H.Q. & Liu, M.C. Release of both CCR4-active and CXCR3-active chemokines during human allergic pulmonary late-phase reactions. J. Allergy Clin. Immunol. 112, 930–934 (2003).

    Article  CAS  Google Scholar 

  27. 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).

    Article  CAS  Google Scholar 

  28. Rankin, J.A. et al. Phenotypic and physiologic characterization of transgenic mice expressing interleukin 4 in the lung: lymphocytic and eosinophilic inflammation without airway hyperreactivity. Proc. Natl. Acad. Sci. USA 93, 7821–7825 (1996).

    Article  CAS  Google Scholar 

  29. Lee, J.J. et al. Interleukin-5 expression in the lung epithelium of transgenic mice leads to pulmonary changes pathognomonic of asthma. J. Exp. Med. 185, 2143–2156 (1997).

    Article  CAS  Google Scholar 

  30. Zhu, Z. et al. Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J. Clin. Invest. 103, 779–788 (1999).

    Article  CAS  Google Scholar 

  31. Lambrecht, B.N. & Hammad, H. Taking our breath away: dendritic cells in the pathogenesis of asthma. Nat. Rev. Immunol. 3, 994–1003 (2003).

    Article  CAS  Google Scholar 

  32. Carpino, N. et al. Absence of an essential role for thymic stromal lymphopoietin receptor in murine B-cell development. Mol. Cell. Biol. 24, 2584–2592 (2004).

    Article  CAS  Google Scholar 

  33. Tsitoura, D.C. et al. Respiratory infection with influenza A virus interferes with the induction of tolerance to aeroallergens. J. Immunol. 165, 3484–3491 (2000).

    Article  CAS  Google Scholar 

  34. Brawand, P. et al. Murine plasmacytoid pre-dendritic cells generated from Flt3 ligand-supplemented bone marrow cultures are immature APCs. J. Immunol. 169, 6711–6719 (2002).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank J.N. Ihle (St. Jude Children's Research Hospital) for providing Tslpr−/− mice, and H. Sage and G. Nepom for critical reading of the manuscript. Supported by the National Institutes of Health (AI44259 to S.F.Z.) and the American Lung Association of Washington (B.Z.).

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Correspondence to Steven F Ziegler.

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M.R.C. and T.D.S. are employees of Amgen.

Supplementary information

Supplementary Fig. 1

Alveolar macrophages from Tslpr−/− mice, sensitized and challenged with OVA, are less activated than those from Tslpr+/+ mice. (PDF 903 kb)

Supplementary Fig. 2

The SPC-Tslpr-transgenic mice showed no obvious abnormalities in the development of immune system at 2-3 months of age when lung showed fully asthma-like phenotypes. (PDF 752 kb)

Supplementary Fig. 3

CD4+ T cells in the BAL of SPC-Tslpr-mice increased CCR4 expression while losing lymph node homing receptors CD62L and CCR7. (PDF 149 kb)

Supplementary Fig. 4

Normal littermate control (NLC) mice showed no signs of airway remodeling. (PDF 917 kb)

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Zhou, B., Comeau, M., Smedt, T. et al. Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice. Nat Immunol 6, 1047–1053 (2005). https://doi.org/10.1038/ni1247

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