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Resolution of inflammation by interleukin-9-producing type 2 innate lymphoid cells

Nature Medicine volume 23, pages 938–944 (2017)Cite this article

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Abstract

Inflammatory diseases such as arthritis are chronic conditions that fail to resolve spontaneously. While the cytokine and cellular pathways triggering arthritis are well defined, those responsible for the resolution of inflammation are incompletely characterized. Here we identified interleukin (IL)-9-producing type 2 innate lymphoid cells (ILC2s) as the mediators of a molecular and cellular pathway that orchestrates the resolution of chronic inflammation. In mice, the absence of IL-9 impaired ILC2 proliferation and activation of regulatory T (Treg) cells, and resulted in chronic arthritis with excessive cartilage destruction and bone loss. In contrast, treatment with IL-9 promoted ILC2-dependent Treg activation and effectively induced resolution of inflammation and protection of bone. Patients with rheumatoid arthritis in remission exhibited high numbers of IL-9+ ILC2s in joints and the circulation. Hence, fostering IL-9-mediated ILC2 activation may offer a novel therapeutic approach inducing resolution of inflammation rather than suppression of inflammatory responses.

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Figure 1: Chronic arthritis in Il9-deficient mice.
Figure 2: IL-9 accelerates the resolution of arthritis.
Figure 3: Altered TH17 and Treg responses in arthritic Il9−/− mice.
Figure 4: ILC2s sustain the suppressive capacity of Treg cells by co-stimulation via ICOSL–ICOS and GITRL–GITR.
Figure 5: IL-9 during resolution of human arthritis.

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Acknowledgements

The authors thank M. Pascual, K. Dreissigacker, R. Kleinlein, M. Comazzi, D. Weidner and B. Happich for excellent technical assistance. We thank U. Appelt and M. Mroz of the Core Unit Cell Sorting and Immunomonitoring Erlangen for cell sorting. This work was supported by the Deutsche Forschungsgemeinschaft (RA 2506/3-1 and RA 2506/4-1 to A.R.; DI 1537/5-1, DI 1537/7-1, DI 1537/8-1, DI 1537/9-1, AK 144/2-1 and DI 1537/11-1 to J.H.W.D.; SCHE 1583/7-1 to G.S.; SPP1468-IMMUNOBONE and CRC1181 to G.S. and J.H.W.D.), the Bundesministerium für Bildung und Forschung (METHARTHROS to G.S. and J.H.W.D.), the Marie Curie project OSTEOIMMUNE (to G.S. and J.H.W.D.), the TEAM project of the European Union and the IMI-funded project RTCure (to G.S.), Else Kröner-Fresenius-Stiftung 2014_A184 (to A.R.), the Wilhelm Sander Foundation (2013.056.1 to J.H.W.D.), the Interdisciplinary Centre for Clinical Research, Erlangen (A64 to J.H.W.D.; J40 to A.R.), the ELAN Fonds of the Universitätsklinikum Erlangen (16-10-05-1 to A.R.), the Career Support Award of Medicine of the Ernst Jung Foundation (to J.H.W.D.), SNF Sinergia CRSII3_154490 (to O.D.), the UK MRC (UI015178805; to A.N.J.M.), the Wellcome Trust (100963/Z/13/Z to A.N.J.M.) and US NIH grant AI057459 (to M.H.K.).

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Authors and Affiliations

  1. Department of Internal Medicine 3–Rheumatology and Immunology, Friedrich Alexander University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany

    Simon Rauber, Markus Luber, Stefanie Weber, Lisa Maul, Alina Soare, Thomas Wohlfahrt, Neng-Yu Lin, Katharina Dietel, Aline Bozec, Martin Herrmann, Mario M Zaiss, Georg Schett, Jörg H W Distler & Andreas Ramming

  2. Herman B Wells Center for Pediatric Research, Indianapolis, Indiana, USA

    Mark H Kaplan

  3. Department of Internal Medicine 1, Friedrich Alexander University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany

    Benno Weigmann, Markus F Neurath & Stefan Wirtz

  4. Molecular Rheumatology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland

    Ursula Fearon

  5. Centre for Arthritis and Rheumatic Diseases, St. Vincent's University Hospital, Dublin, Ireland

    Douglas J Veale

  6. Departamento de Reumatología, Hospital Clínic de Barcelona e IDIBAPS, Barcelona, Spain

    Juan D Cañete

  7. Division of Rheumatology, University Hospital Zurich, Zurich, Switzerland

    Oliver Distler

  8. Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London and Barts Health NHS Trust, London, UK

    Felice Rivellese & Costantino Pitzalis

  9. MRC Laboratory of Molecular Biology, Cambridge, UK

    Andrew N J McKenzie

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Contributions

Design of the study: S.R., G.S., J.H.W.D., A.R. Acquisition of data: S.R., M.L., S. Weber, L.M., A.S., T.W., N.-Y.L., K.D., M.G., A.R. Interpretation of data: S.R., A.B., M.H., A.N.J.M., B.W., M.M.Z., U.F., D.J.V., J.D.C., O.D., F.R., C.P., S. Wirtz, M.F.N., G.S., J.H.W.D., A.R. Support of material: A.B., M.H., M.H.K., B.W., U.F., D.J.V., J.D.C., O.D., F.R., C.P., M.F.N., A.N.J.M., S. Wirtz. Manuscript preparation: S.R., G.S., J.H.W.D., A.R.

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Correspondence to Andreas Ramming.

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Rauber, S., Luber, M., Weber, S. et al. Resolution of inflammation by interleukin-9-producing type 2 innate lymphoid cells. Nat Med 23, 938–944 (2017). https://doi.org/10.1038/nm.4373

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