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Interleukin 18–independent engagement of interleukin 18 receptor-α is required for autoimmune inflammation

Nature Immunology volume 7, pages 946–953 (2006)Cite this article

Abstract

T helper type 1 (TH1) lymphocytes are considered to be the main pathogenic cell type responsible for organ-specific autoimmune inflammation. As interleukin 18 (IL-18) is a cofactor with IL-12 in promoting TH1 cell development, we examined the function of IL-18 and its receptor, IL-18R, in autoimmune central nervous system inflammation. Similar to IL-12-deficient mice, IL-18-deficient mice were susceptible to experimental autoimmune encephalomyelitis. In contrast, IL-18Rα-deficient mice were resistant to experimental autoimmune encephalomyelitis, indicating involvement of an IL-18Rα ligand other than IL-18 with encephalitogenic properties. Moreover, engagement of IL-18Rα on antigen-presenting cells was required for the generation of pathogenic IL-17-producing T helper cells. Thus, IL-18 and TH1 cells are dispensable, whereas IL-18Rα and IL-17-producing T helper cells are required, for autoimmune central nervous system inflammation.

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Figure 1: IL-18 is not required for EAE induction.
Figure 2: IL-18 is required for mitogen- but not antigen-driven TH1 development.
Figure 3: Discordant EAE progression in Il18−/− and Il18r1−/− mice.
Figure 4: Histopathology of Il18−/− and Il18r1−/− mice.
Figure 5: Tissue invasion at preclinical stages is not affected by IL-18Rα.
Figure 6: TH-17 cell induction depends on IL-18Rα but not IL-18.
Figure 7: IL-18Rα deficiency specifically affects nonlymphocytic leukocytes.
Figure 8: IL-18Rα engagement promotes the production of IL-23p40.

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Acknowledgements

We thank H. Hofstetter (University of Wurzburg, Wurzburg, Germany) and V. Woertmann (University of Zurich, Zurich, Switzerland) for technical assistance; and E. Saller and T. Buch (University of Zurich, Zurich, Switzerland) for critical review of this manuscript. Supported by the Swiss National Science Foundation (B.B.), the National Center for Competence in Research (B.B.), the Swiss Multiple Sclerosis Society (B.B.), the Hertie Foundation (B.B. & M.P.), Serono Pharmaceuticals Geneva (B.B.), the Center for Neuroscience Research in Zurich (I.G.), Roche Research Foundation (EU) and the National Multiple Sclerosis Society (Harry Weaver Neuroscience scholar; B.B.).

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Authors and Affiliations

  1. Neuroimmunology Unit, Neurology Clinic, University of Zurich, Zurich, 8057, Switzerland

    Ilona Gutcher, Eduard Urich & Burkhard Becher

  2. Institute of Neuropathology, Georg-August-University, Gottingen, D-37075, Germany

    Karina Wolter & Marco Prinz

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  1. Ilona Gutcher
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Contributions

I.G. did all the experiments unless stated otherwise; E.U. helped with the generation of experimentation and analysis of bone marrow–chimeric mice; K.W. and M.P. analyzed the histopathological data; and B.B. and I.G. designed all the experiments and prepared the manuscript.

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Correspondence to Burkhard Becher.

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Supplementary information

Supplementary Fig. 1

Il18−/− LN cells do not produce IL-18. (PDF 350 kb)

Supplementary Fig. 2

CD4+ T cells from Il18−/− and Il18r1−/− mice are capable of IFN-γ production. (PDF 340 kb)

Supplementary Fig. 3

Analysis of inflammatory infiltrates, cytokines and chemokines in MOG(35-55)-immunized mice. (PDF 1188 kb)

Supplementary Fig. 4

Intracellular staining for IL-17 and IFN-γ. (PDF 347 kb)

Supplementary Table 1

IL-18Rα Ab does not affect the cell composition of the peripheral immune compartment. (PDF 345 kb)

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Gutcher, I., Urich, E., Wolter, K. et al. Interleukin 18–independent engagement of interleukin 18 receptor-α is required for autoimmune inflammation. Nat Immunol 7, 946–953 (2006). https://doi.org/10.1038/ni1377

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