House dust mite allergen induces asthma via Toll-like receptor 4 triggering of airway structural cells


Barrier epithelial cells and airway dendritic cells (DCs) make up the first line of defense against inhaled substances such as house dust mite (HDM) allergen and endotoxin (lipopolysaccharide, LPS). We hypothesized that these cells need to communicate with each other to cause allergic disease. We show in irradiated chimeric mice that Toll-like receptor 4 (TLR4) expression on radioresistant lung structural cells, but not on DCs, is necessary and sufficient for DC activation in the lung and for priming of effector T helper responses to HDM. TLR4 triggering on structural cells caused production of the innate proallergic cytokines thymic stromal lymphopoietin, granulocyte-macrophage colony–stimulating factor, interleukin-25 and interleukin-33. The absence of TLR4 on structural cells, but not on hematopoietic cells, abolished HDM-driven allergic airway inflammation. Finally, inhalation of a TLR4 antagonist to target exposed epithelial cells suppressed the salient features of asthma, including bronchial hyperreactivity. Our data identify an innate immune function of airway epithelial cells that drives allergic inflammation via activation of mucosal DCs.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Assessment of the reconstitution rate of chimeric mice.
Figure 2: TLR4 expression on radioresistant stromal cells is necessary and sufficient for recruitment of DCs to the lungs in response to LPS.
Figure 3: TLR4 expression on radioresistant stromal cells is necessary and sufficient for activation of mucosal DCs.
Figure 4: TLR4 expression on airway structural cells is necessary and sufficient for an innate immune response to HDM allergen.
Figure 5: TLR4 expression on airway structural cells is necessary and sufficient for HDM-driven TH2 responses and allergic inflammation.
Figure 6: Intrapulmonary delivery of a TLR4 antagonist reduces HDM-driven inflammation and airway hyper-responsiveness.


  1. 1

    Barnes, P.J. Immunology of asthma and chronic obstructive pulmonary disease. Nat. Rev. Immunol. 8, 183–192 (2008).

    CAS  Article  Google Scholar 

  2. 2

    Vermaelen, K.Y., Carro-Muino, I., Lambrecht, B.N. & Pauwels, R.A. Specific migratory dendritic cells rapidly transport antigen from the airways to the thoracic lymph nodes. J. Exp. Med. 193, 51–60 (2001).

    CAS  Article  Google Scholar 

  3. 3

    Stampfli, M.R. et al. GM-CSF transgene expression in the airway allows aerosolized ovalbumin to induce allergic sensitization in mice. J. Clin. Invest. 102, 1704–1714 (1998).

    CAS  Article  Google Scholar 

  4. 4

    Ziegler, S.F. & Liu, Y.J. Thymic stromal lymphopoietin in normal and pathogenic T cell development and function. Nat. Immunol. 7, 709–714 (2006).

    CAS  Article  Google Scholar 

  5. 5

    Sha, Q. et al. Activation of airway epithelial cells by Toll-like receptor agonists. Am. J. Respir. Cell Mol. Biol. 31, 358–364 (2004).

    Article  Google Scholar 

  6. 6

    Guillot, L. et al. Response of human pulmonary epithelial cells to lipopolysaccharide involves Toll-like receptor 4 (TLR4)-dependent signaling pathways: evidence for an intracellular compartmentalization of TLR4. J. Biol. Chem. 279, 2712–2718 (2004).

    CAS  Article  Google Scholar 

  7. 7

    Skerrett, S.J. et al. Respiratory epithelial cells regulate lung inflammation in response to inhaled endotoxin. Am. J. Physiol. Lung Cell. Mol. Physiol. 287, L143–L152 (2004).

    CAS  Article  Google Scholar 

  8. 8

    Hammad, H. & Lambrecht, B.N. Dendritic cells and epithelial cells: linking innate and adaptive immunity in asthma. Nat. Rev. Immunol. 8, 193–204 (2008).

    CAS  Article  Google Scholar 

  9. 9

    Saito, T. et al. Expression of Toll-like receptor 2 and 4 in lipopolysaccharide-induced lung injury in mouse. Cell Tissue Res. 321, 75–88 (2005).

    CAS  Article  Google Scholar 

  10. 10

    Berndt, A. et al. Elevated amount of Toll-like receptor 4 mRNA in bronchial epithelial cells is associated with airway inflammation in horses with recurrent airway obstruction. Am. J. Physiol. Lung Cell. Mol. Physiol. 292, L936–L943 (2007).

    CAS  Article  Google Scholar 

  11. 11

    Trompette, A. et al. Allergenicity resulting from functional mimicry of a Toll-like receptor complex protein. Nature 457, 585–588 (2009).

    CAS  Article  Google Scholar 

  12. 12

    Reis E Sousa, C. Dendritic cells in a mature age. Nat. Rev. Immunol. 6, 476–483 (2006).

    CAS  Article  Google Scholar 

  13. 13

    Braun-Fahrlander, C. et al. Environmental exposure to endotoxin and its relation to asthma in school-age children. N. Engl. J. Med. 347, 869–877 (2002).

    Article  Google Scholar 

  14. 14

    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).

    CAS  Article  Google Scholar 

  15. 15

    Fattouh, R. et al. House dust mite facilitates ovalbumin-specific allergic sensitization and airway inflammation. Am. J. Respir. Crit. Care Med. 172, 314–321 (2005).

    Article  Google Scholar 

  16. 16

    Cates, E.C. et al. Intranasal exposure of mice to house dust mite elicits allergic airway inflammation via a GM-CSF–mediated mechanism. J. Immunol. 173, 6384–6392 (2004).

    CAS  Article  Google Scholar 

  17. 17

    Fallon, P.G. et al. Identification of an interleukin (IL)-25–dependent cell population that provides IL-4, IL-5, and IL-13 at the onset of helminth expulsion. J. Exp. Med. 203, 1105–1116 (2006).

    CAS  Article  Google Scholar 

  18. 18

    Kondo, Y. et al. 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 (2008).

    CAS  Article  Google Scholar 

  19. 19

    Zhou, B. et al. Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice. Nat. Immunol. 6, 1047–1053 (2005).

    CAS  Article  Google Scholar 

  20. 20

    Eisenbarth, S.C. et al. Lipopolysaccharide-enhanced, Toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen. J. Exp. Med. 196, 1645–1651 (2002).

    CAS  Article  Google Scholar 

  21. 21

    Nolte, M.A., Leibundgut-Landmann, S., Joffre, O. & Sousa, C.R. Dendritic cell quiescence during systemic inflammation driven by LPS stimulation of radioresistant cells in vivo. J. Exp. Med. 204, 1487–1501 (2007).

    CAS  Article  Google Scholar 

  22. 22

    Poynter, M.E., Irvin, C.G. & Janssen-Heininger, Y.M. A prominent role for airway epithelial NF-κB activation in lipopolysaccharide-induced airway inflammation. J. Immunol. 170, 6257–6265 (2003).

    CAS  Article  Google Scholar 

  23. 23

    Noulin, N. et al. Both hematopoietic and resident cells are required for MyD88-dependent pulmonary inflammatory response to inhaled endotoxin. J. Immunol. 175, 6861–6869 (2005).

    CAS  Article  Google Scholar 

  24. 24

    Lorenz, E. et al. Genes other than TLR4 are involved in the response to inhaled LPS. Am. J. Physiol. Lung Cell. Mol. Physiol. 281, L1106–L1114 (2001).

    CAS  Article  Google Scholar 

  25. 25

    Pichavant, M. et al. Asthmatic bronchial epithelium activated by the proteolytic allergen Der p 1 increases selective dendritic cell recruitment. J. Allergy Clin. Immunol. 115, 771–778 (2005).

    CAS  Article  Google Scholar 

  26. 26

    Nathan, A.T., Peterson, E.A., Chakir, J. & Wills-Karp, M. Innate immune responses of airway epithelium to house dust mite are mediated through β-glucan–dependent pathways. J. Allergy Clin. Immunol. published online, doi:10.1016/j.jaci.2008.12.006 (27 January 2009).

  27. 27

    Robays, L.J. et al. Chemokine receptor CCR2 but not CCR5 or CCR6 mediates the increase in pulmonary dendritic cells during allergic airway inflammation. J. Immunol. 178, 5305–5311 (2007).

    CAS  Article  Google Scholar 

  28. 28

    Geissmann, F., Jung, S. & Littman, D.R. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19, 71–82 (2003).

    CAS  Article  Google Scholar 

  29. 29

    Veres, T.Z. et al. Spatial interactions between dendritic cells and sensory nerves in allergic airway inflammation. Am. J. Respir. Cell Mol. Biol. 37, 553–561 (2007).

    CAS  Article  Google Scholar 

  30. 30

    Bajenoff, M. et al. Stromal cell networks regulate lymphocyte entry, migration and territoriality in lymph nodes. Immunity 25, 989–1001 (2006).

    CAS  Article  Google Scholar 

  31. 31

    Hammad, H. & Lambrecht, B.N. Lung dendritic cell migration. Adv. Immunol. 93, 265–278 (2007).

    CAS  Article  Google Scholar 

  32. 32

    Stumbles, P.A. et al. Resting respiratory tract dendritic cells preferentially stimulate T helper cell type 2 (TH2) responses and require obligatory cytokine signals for induction of TH1 immunity. J. Exp. Med. 188, 2019–2031 (1998).

    CAS  Article  Google Scholar 

  33. 33

    Bilyk, N. & Holt, P.G. Inhibition of the immunosuppressive activity of resident pulmonary alveolar macrophages by granulocyte/macrophage colony–stimulating factor. J. Exp. Med. 177, 1773–1777 (1993).

    CAS  Article  Google Scholar 

  34. 34

    Piggott, D.A. et al. MyD88-dependent induction of allergic TH2 responses to intranasal antigen. J. Clin. Invest. 115, 459–467 (2005).

    CAS  Article  Google Scholar 

  35. 35

    Liu, Y.J. Thymic stromal lymphopoietin: master switch for allergic inflammation. J. Exp. Med. 203, 269–273 (2006).

    Article  Google Scholar 

  36. 36

    Angkasekwinai, P. et al. Interleukin 25 promotes the initiation of proallergic type 2 responses. J. Exp. Med. 204, 1509–1517 (2007).

    CAS  Article  Google Scholar 

  37. 37

    Sokol, C.L., Barton, G.M., Farr, A.G. & Medzhitov, R. A mechanism for the initiation of allergen-induced T helper type 2 responses. Nat. Immunol. 9, 310–318 (2008).

    CAS  Article  Google Scholar 

  38. 38

    Schmitz, J. et al. IL-33, an interleukin-1–like cytokine that signals via the IL-1 receptor–related protein ST2 and induces T helper type 2–associated cytokines. Immunity 23, 479–490 (2005).

    CAS  Article  Google Scholar 

  39. 39

    Wills-Karp, M. et al. Interleukin-13: central mediator of allergic asthma. Science 282, 2258–2261 (1998).

    CAS  Article  Google Scholar 

  40. 40

    Beutler, B. & Poltorak, A. The sole gateway to endotoxin response: how LPS was identified as Tlr4, and its role in innate immunity. Drug Metab. Dispos. 29, 474–478 (2001).

    CAS  PubMed  Google Scholar 

  41. 41

    Boes, M. et al. T-cell engagement of dendritic cells rapidly rearranges MHC class II transport. Nature 418, 983–988 (2002).

    CAS  Article  Google Scholar 

  42. 42

    Matute-Bello, G. et al. Optimal timing to repopulation of resident alveolar macrophages with donor cells following total body irradiation and bone marrow transplantation in mice. J. Immunol. Methods 292, 25–34 (2004).

    CAS  Article  Google Scholar 

  43. 43

    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).

    CAS  Google Scholar 

  44. 44

    Van Rijt, L.S. et al. A rapid flow cytometric method for determining the cellular composition of bronchoalveolar lavage fluid cells in mouse models of asthma. J. Immunol. Methods 288, 111–121 (2004).

    CAS  Article  Google Scholar 

  45. 45

    Hammad, H. et al. Activation of the D prostanoid 1 receptor suppresses asthma by modulation of lung dendritic cell function and induction of regulatory T cells. J. Exp. Med. 204, 357–367 (2007).

    CAS  Article  Google Scholar 

Download references


MHCII-EGFP knock-in mice were provided by H. Ploegh (Harvard Medical School). B.N.L. is a recipient of an Odysseus grant from the Flemish government. We wish to thank T. Boterberg for help with mouse irradiation and S. De Prijck and M. Van Heerswinghel for help with experiments.

Author information




H.H., M.C., M.A.W. and F.P. performed and analyzed experiments; M.C. and R.N.G. were instrumental in setting up the live dual-photon imaging; R.N.G. supervised the work at the US National Institutes of Health and B.N.L. supervised the work at Ghent University. All authors contributed collectively to the conception of the project, to the planning, discussion and interpretation of experiments, and to the writing of the paper.

Corresponding author

Correspondence to Bart N Lambrecht.

Supplementary information

Supplementary Text and Figures

Supplementary Figs. 1–4, Supplementary Table 1 and Supplementary Methods (PDF 859 kb)

Supplementary Movie 1

In situ behavior of non-stimulated airway DCs. Video of a tracheal explant from a WT→WT mouse given PBS intratracheally. The trachea was explanted, stained with Hoechst (blue) and immobilized. Total time, 26 min. Playback speed, 120 ×. Bar, 70 μm. (AVI 1065 kb)

Supplementary Movie 2

In situ behavior of LPS-activated airway DCs in WT→WT chimeric mice. Video of a tracheal explant from a WT→WT chimeric mouse given LPS intratracheally. The trachea was explanted, stained with Hoechst (blue) and immobilized. Total time, 26 min. Playback speed, 120 ×. Bar, 70 μm. (AVI 1072 kb)

Supplementary Movie 3

In situ behavior of LPS-activated airway DCs in WT→Tlr4−/− chimeric mice. Video of a tracheal explant from an MHCII-EGFP mouse given LPS intratracheally. The trachea was explanted, stained with Hoechst (blue) and immobilized. Total time, 26 min. Playback speed, 120 ×. Bar, 70 μm. (AVI 903 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hammad, H., Chieppa, M., Perros, F. et al. House dust mite allergen induces asthma via Toll-like receptor 4 triggering of airway structural cells. Nat Med 15, 410–416 (2009).

Download citation

Further reading


Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing