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Unique functions of the type II interleukin 4 receptor identified in mice lacking the interleukin 13 receptor α1 chain

Abstract

The interleukin 4 receptor (IL-4R) is a central mediator of T helper type 2 (TH2)–mediated disease and associates with either the common γ-chain to form the type I IL-4R or with the IL-13R α1 chain (IL-13Rα1) to form the type II IL-4R. Here we used Il13ra1−/− mice to characterize the distinct functions of type I and type II IL-4 receptors in vivo. In contrast to Il4ra−/− mice, which have weak TH2 responses, Il13ra1−/− mice had exacerbated TH2 responses. Il13ra1−/− mice showed much less mortality after infection with Schistosoma mansoni and much more susceptibility to Nippostrongylus brasiliensis. IL-13Rα1 was essential for allergen-induced airway hyperreactivity and mucus hypersecretion but not for fibroblast or alternative macrophage activation. Thus, type I and II IL-4 receptors exert distinct effects on immune responses.

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Figure 1: Characterization of Il13ra1−/− mice.
Figure 2: Macrophages respond to IL-4 but not IL-13 in the absence of type II IL-4 receptor signaling.
Figure 3: Serum immunoglobulin production by Il13ra1−/− mice chronically infected with S. mansoni.
Figure 4: Cytokine production by liver granuloma–associated lymphocytes after S. mansoni infection.
Figure 5: Attenuated tissue fibrosis in Il13ra1−/− mice.
Figure 6: Gene expression profiles of Il13ra1+/+ and Il13ra1−/− livers after infection with S. mansoni.
Figure 7: Type II IL-4R deficiency protects mice from morbidity after S. mansoni infection.
Figure 8: Impaired expulsion of N. brasiliensis in Il13ra1−/− mice.
Figure 9: Protection from allergen-induced airway hyperreactivity in Il13ra1−/− mice.

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Acknowledgements

We thank R. Thompson, S. White and the animal care technicians for technical assistance; F. Lewis and the Biomedical Research Institute for S. mansoni cercariae; and M. Karow (Regeneron) for discussions. Supported by the intramural research program of the National Institutes of Health–National Institute of Allergy and Infectious Diseases, and Regeneron.

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T.R.R. designed and did experiments and contributed to the manuscript; J.T.P., F.S., M.M.M.-K. and M.S.W. designed and did experiments; A.W.C. and J.F.U. assisted in animal experiments, scoring and data analysis; S.S., D.M.V., A.J.M. and G.D.Y. provided the Il13ra1−/− mice and assisted in writing the manuscript; R.P.D. designed and assisted in experiments; and T.A.W. designed and supervised the project, designed and assisted in experiments, and helped write the manuscript.

Corresponding author

Correspondence to Thomas A Wynn.

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S.S., D.M.V., W.J.M and G.D.Y were employees of Regeneron Pharmaceuticals at the time this work was done.

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Ramalingam, T., Pesce, J., Sheikh, F. et al. Unique functions of the type II interleukin 4 receptor identified in mice lacking the interleukin 13 receptor α1 chain. Nat Immunol 9, 25–33 (2008). https://doi.org/10.1038/ni1544

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