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

Abstract

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.

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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.

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Acknowledgements

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.

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Authors

Contributions

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)

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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). https://doi.org/10.1038/nm.1946

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