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Interleukin-25 induces type 2 cytokine production in a steroid-resistant interleukin-17RB+ myeloid population that exacerbates asthmatic pathology

Nature Medicine volume 18, pages 751–758 (2012)Cite this article

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Abstract

Interleukin-25 (IL-25) is a cytokine associated with allergy and asthma that functions to promote type 2 immune responses at mucosal epithelial surfaces and serves to protect against helminth parasitic infections in the intestinal tract. This study identifies the IL-25 receptor, IL-17RB, as a key mediator of both innate and adaptive pulmonary type 2 immune responses. Allergen exposure upregulated IL-25 and induced type 2 cytokine production in a previously undescribed granulocytic population, termed type 2 myeloid (T2M) cells. Il17rb−/− mice showed reduced lung pathology after chronic allergen exposure and decreased type 2 cytokine production in T2M cells and CD4+ T lymphocytes. Airway instillation of IL-25 induced IL-4 and IL-13 production in T2M cells, demonstrating their importance in eliciting T cell–independent inflammation. The adoptive transfer of T2M cells reconstituted IL-25–mediated responses in Il17rb−/− mice. High-dose dexamethasone treatment did not reduce the IL-25–induced T2M pulmonary response. Finally, a similar IL-4– and IL-13–producing granulocytic population was identified in peripheral blood of human subjects with asthma. These data establish IL-25 and its receptor IL-17RB as targets for innate and adaptive immune responses in chronic allergic airway disease and identify T2M cells as a new steroid-resistant cell population.

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Figure 1: Allergen exposure increases pulmonary IL-25 and IL-17RB expression and recruits bone marrow–derived IL-17RB+ IL-4– and IL-13–producing myeloid cells to the lung.
Figure 2: Il17rb−/− mice are protected from allergen-induced type 2 inflammation, and type 2 cytokine production in CD11b+Gr-1+ myeloid cells is IL-17RB dependent.
Figure 3: T2M cells represent the primary source of type 2 cytokines following pulmonary IL-25 administration.
Figure 4: Patterns of surface receptor expression and a comparison of microarray profiles define T2M cells as a distinct granulocytic subset.
Figure 5: T2M cells are steroid resistant and are sufficient to induce airway pathology in Il17rb−/− mice.
Figure 6: An IL-4– and IL-13–producing population analogous to T2M cells is identifiable in peripheral blood and markedly increased in individuals with asthma.

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Acknowledgements

We thank J. Connett for comments on the manuscript, K. Augusztiny for valuable insight and perspective, members of the Lukacs, Kunkel and Hogaboam labs for many helpful discussions, and the University of Michigan Flow Cytometry and DNA Sequencing Cores for technical assistance. This work was supported by US National Institutes of Health grants R01 HL05178 and R01 HL036302 (to N.W.L.) and National Institute of General Medical Studies grant 3T32GM007863-31S1 (to the University of Michigan Medical Scientist Training Program and B.C.P.). Il17rb−/− mice were provided by A.L. Budelsky (Amgen).

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Authors and Affiliations

  1. Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA

    Bryan C Petersen, Matthew A Schaller & Nicholas W Lukacs

  2. Department of Inflammation, Amgen, Seattle, Washington, USA

    Alison L Budelsky

  3. Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA

    Alan P Baptist

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Contributions

B.C.P. conceived of the study, performed experiments and data analyses and wrote the manuscript. A.L.B. and M.A.S. provided intellectual contributions through technical advice and experimental design. A.P.B. coordinated recruitment of subjects with asthma. N.W.L. conceived of and supervised the study and wrote the manuscript.

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Correspondence to Nicholas W Lukacs.

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Petersen, B., Budelsky, A., Baptist, A. et al. Interleukin-25 induces type 2 cytokine production in a steroid-resistant interleukin-17RB+ myeloid population that exacerbates asthmatic pathology. Nat Med 18, 751–758 (2012). https://doi.org/10.1038/nm.2735

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