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Cytosolic RIG-I–like helicases act as negative regulators of sterile inflammation in the CNS

Nature Neuroscience volume 15, pages 98–106 (2012)Cite this article

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Abstract

The action of cytosolic RIG-I–like helicases (RLHs) in the CNS during autoimmunity is largely unknown. Using a mouse model of multiple sclerosis, we found that mice lacking the RLH adaptor IPS-1 developed exacerbated disease that was accompanied by markedly higher inflammation, increased axonal damage and elevated demyelination with increased encephalitogenic immune responses. Furthermore, activation of RLH ligands such as 5′-triphosphate RNA oligonucleotides decreased CNS inflammation and improved clinical signs of disease. RLH stimulation repressed the maintenance and expansion of committed TH1 and TH17 cells, whereas T-cell differentiation was not altered. Notably, TH1 and TH17 suppression required type I interferon receptor engagement on dendritic cells, but not on macrophages or microglia. These results identify RLHs as negative regulators of TH1 and TH17 responses in the CNS, demonstrate a protective role of the RLH pathway for brain inflammation, and establish oligonucleotide ligands of RLHs as potential therapeutics for the treatment of multiple sclerosis.

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Figure 1: IPS-1 signaling is critical for the effector phase of autoimmunity, CNS pathology and the modulation of encephalitogenic cytokines.
Figure 2: Activation of the cytosolic helicases modulates CNS autoimmunity through an IFNAR-dependent pathway.
Figure 3: Induction of type I interferon–dependent genes and local suppression of the TH1 and TH17 immune response in the CNS following RIG-I and MDA5 activation.
Figure 4: Type I IFN induction by dsRNAs in the hematopoietic compartment is cell-type specific and requires RIG-I and MDA5, but not TLR7.
Figure 5: IFNAR signaling on dendritic cells rather than on monocytic cells is required for dsRNA-mediated suppression of CNS autoimmunity.
Figure 6: RLH stimulation interferes with TH1 and TH17 expansion and survival.
Figure 7: Engagement of RIG-I and MDA5 does not shape normal T-cell differentiation.

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Acknowledgements

We thank A.-K. Gersmann, M. Oberle, D. Kreuz and K. Wolter for excellent technical assistance, A. Diefenbach, H. Jumaa and H. Eibel for scientific advice and S. Brendecke for critical reading. This manuscript is dedicated to Benedikt Volk, former director of the Department of Neuropathology in Freiburg, who devoted his whole life to the exploration of the brain, as an eternal source of inspiration.

This work was supported by KFO177, SFB670 and SFB704 of the German Research Council (DFG), and a Biofuture and a Go-Bio grant of the Bundesministerium für Bildung und Forschung (BMBF) to G.H., a DFG Graduiertenkolleg 1202 fellowship to C.M., the Center of Integrated Protein Science Munich, a research professorship and a “BayImmunet” grant to S.E. M.P. was supported by the BMBF-funded Competence Network of Multiple Sclerosis, the Competence Network of Neurodegenerative Disorders, the Center of Chronic Immunodeficiency (CCI), the DFG (SFB 620, FOR1336 and PR 577/8-1) and the Gemeinnützige Hertie-Foundation.

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  1. Angela Dann and Hendrik Poeck: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neuropathology, University of Freiburg, Freiburg, Germany

    Angela Dann, Stefanie Gaupp, Katrin Kierdorf, Markus Knust, Klaus-Peter Knobeloch & Marco Prinz

  2. Faculty of Biology, University of Freiburg, Freiburg, Germany

    Angela Dann, Katrin Kierdorf & Markus Knust

  3. Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, Bonn, Germany

    Hendrik Poeck, Stefan Endres & Gunther Hartmann

  4. III. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

    Hendrik Poeck

  5. Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany

    Andrew L Croxford & Ari Waisman

  6. Department of Hematology and Oncology, University Medical Center Freiburg, Freiburg, Germany

    Dietmar Pfeifer

  7. Department of Radiation Oncology, University of Munich, Munich, Germany

    Cornelius Maihoefer

  8. Center of Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Internal Medicine, University of Munich, Munich, Germany

    Stefan Endres

  9. Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research, Braunschweig and the Hannover Medical School, Hannover, Germany

    Ulrich Kalinke

  10. Department of Neurology, Inflammatory Disorders of the Nervous System and Neuro-oncology, University of Münster, Münster, Germany

    Sven G Meuth & Heinz Wiendl

  11. Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Japan

    Shizuo Akira

  12. BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany

    Marco Prinz

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Contributions

A.D., H.P., A.L.C., S.G., K.K., M.K., D.P., C.M., S.G.M., H.W. and K.-P.K. conducted the experiments. U.K., S.E., S.A. and A.W. contributed to the in vivo studies and provided mice or reagents. A.D., H.P., G.H. and M.P. wrote the manuscript. M.P. supervised the project.

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Correspondence to Marco Prinz.

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Dann, A., Poeck, H., Croxford, A. et al. Cytosolic RIG-I–like helicases act as negative regulators of sterile inflammation in the CNS. Nat Neurosci 15, 98–106 (2012). https://doi.org/10.1038/nn.2964

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