Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Steinman, L. A brief history of TH17, the first major revision in the TH1/TH2 hypothesis of T cell–mediated tissue damage. Nat. Med. 13, 139–145 (2007).

    Article  CAS  Google Scholar 

  2. Ivanov, I.I. et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–1133 (2006).

    Article  CAS  Google Scholar 

  3. Komiyama, Y. et al. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J. Immunol. 177, 566–573 (2006).

    Article  CAS  Google Scholar 

  4. Hofstetter, H.H. et al. Therapeutic efficacy of IL-17 neutralization in murine experimental autoimmune encephalomyelitis. Cell. Immunol. 237, 123–130 (2005).

    Article  CAS  Google Scholar 

  5. Langrish, C.L. et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201, 233–240 (2005).

    Article  CAS  Google Scholar 

  6. Tzartos, J.S. et al. Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am. J. Pathol. 172, 146–155 (2008).

    Article  CAS  Google Scholar 

  7. Bettelli, E. et al. Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis. J. Exp. Med. 200, 79–87 (2004).

    Article  CAS  Google Scholar 

  8. Stromnes, I.M., Cerretti, L.M., Liggitt, D., Harris, R.A. & Goverman, J.M. Differential regulation of central nervous system autoimmunity by TH1 and TH17 cells. Nat. Med. 14, 337–342 (2008).

    Article  CAS  Google Scholar 

  9. Kroenke, M.A., Carlson, T.J., Andjelkovic, A.V. & Segal, B.M. IL-12– and IL-23–modulated T cells induce distinct types of EAE based on histology, CNS chemokine profile, and response to cytokine inhibition. J. Exp. Med. 205, 1535–1541 (2008).

    Article  CAS  Google Scholar 

  10. Heppner, F.L. et al. Experimental autoimmune encephalomyelitis repressed by microglial paralysis. Nat. Med. 11, 146–152 (2005).

    Article  CAS  Google Scholar 

  11. Fierz, W., Endler, B., Reske, K., Wekerle, H. & Fontana, A. Astrocytes as antigen-presenting cells. I. Induction of Ia antigen expression on astrocytes by T cells via immune interferon and its effect on antigen presentation. J. Immunol. 134, 3785–3793 (1985).

    CAS  PubMed  Google Scholar 

  12. Kawai, T. & Akira, S. The roles of TLRs, RLRs and NLRs in pathogen recognition. Int. Immunol. 21, 317–337 (2009).

    Article  CAS  Google Scholar 

  13. Matzinger, P. Tolerance, danger, and the extended family. Annu. Rev. Immunol. 12, 991–1045 (1994).

    Article  CAS  Google Scholar 

  14. Akira, S., Uematsu, S. & Takeuchi, O. Pathogen recognition and innate immunity. Cell 124, 783–801 (2006).

    Article  CAS  Google Scholar 

  15. Pichlmair, A. & Reis e Sousa, C. Innate recognition of viruses. Immunity 27, 370–383 (2007).

    Article  CAS  Google Scholar 

  16. Sabbah, A. et al. Activation of innate immune antiviral responses by Nod2. Nat. Immunol. 10, 1073–1080 (2009).

    Article  CAS  Google Scholar 

  17. Vilaysane, A. & Muruve, D.A. The innate immune response to DNA. Semin. Immunol. 21, 208–214 (2009).

    Article  CAS  Google Scholar 

  18. Schlee, M. et al. Recognition of 5′ triphosphate by RIG-I helicase requires short blunt double-stranded RNA as contained in panhandle of negative-strand virus. Immunity 31, 25–34 (2009).

    Article  CAS  Google Scholar 

  19. Hornung, V. et al. 5′-triphosphate RNA is the ligand for RIG-I. Science 314, 994–997 (2006).

    Article  Google Scholar 

  20. Pichlmair, A. et al. Activation of MDA5 requires higher order RNA structures generated during virus infection. J. Virol. 83, 10761–10769 (2009).

    Article  CAS  Google Scholar 

  21. Kato, H. et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441, 101–105 (2006).

    Article  CAS  Google Scholar 

  22. Kawai, T. et al. IPS-1, an adaptor triggering RIG-I– and Mda5-mediated type I interferon induction. Nat. Immunol. 6, 981–988 (2005).

    Article  CAS  Google Scholar 

  23. Xu, L.G. et al. VISA is an adapter protein required for virus-triggered IFN-β signaling. Mol. Cell 19, 727–740 (2005).

    Article  CAS  Google Scholar 

  24. Meylan, E. et al. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437, 1167–1172 (2005).

    Article  CAS  Google Scholar 

  25. Seth, R.B., Sun, L., Ea, C.K. & Chen, Z.J. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-κB and IRF 3. Cell 122, 669–682 (2005).

    Article  CAS  Google Scholar 

  26. Wang, Y. et al. Rig-I−/− mice develop colitis associated with downregulation of Gα i2. Cell Res. 17, 858–868 (2007).

    Article  CAS  Google Scholar 

  27. Smyth, D.J. et al. Shared and distinct genetic variants in type 1 diabetes and celiac disease. N. Engl. J. Med. 359, 2767–2777 (2008).

    Article  CAS  Google Scholar 

  28. Nejentsev, S., Walker, N., Riches, D., Egholm, M. & Todd, J.A. Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science 324, 387–389 (2009).

    Article  CAS  Google Scholar 

  29. Sutton, C.E. et al. Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity 31, 331–341 (2009).

    Article  CAS  Google Scholar 

  30. Guo, B., Chang, E.Y. & Cheng, G. The type I IFN induction pathway constrains Th17-mediated autoimmune inflammation in mice. J. Clin. Invest. 118, 1680–1690 (2008).

    Article  CAS  Google Scholar 

  31. Prinz, M. et al. Distinct and nonredundant in vivo functions of IFNAR on myeloid cells limit autoimmunity in the central nervous system. Immunity 28, 675–686 (2008).

    Article  CAS  Google Scholar 

  32. Mitsdoerffer, M. & Kuchroo, V. New pieces in the puzzle: how does interferon-beta really work in multiple sclerosis? Ann. Neurol. 65, 487–488 (2009).

    Article  Google Scholar 

  33. Prinz, M. & Kalinke, U. New lessons about old molecules: how type I interferons shape Th1/Th17-mediated autoimmunity in the CNS. Trends Mol. Med. 16, 379–386 (2010).

    Article  CAS  Google Scholar 

  34. Mildner, A. et al. CCR2+Ly-6Chi monocytes are crucial for the effector phase of autoimmunity in the central nervous system. Brain 132, 2487–2500 (2009).

    Article  Google Scholar 

  35. Prinz, M. & Priller, J. Tickets to the brain: role of CCR2 and CX(3)CR1 in myeloid cell entry in the CNS. J. Neuroimmunol. 224, 80–84 (2010).

    Article  CAS  Google Scholar 

  36. Prinz, M., Priller, J., Sisodia, S.S. & Ransohoff, R.M. Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nat. Neurosci. 14, 1227–1235 (2011).

    Article  CAS  Google Scholar 

  37. Cucak, H., Yrlid, U., Reizis, B., Kalinke, U. & Johansson-Lindbom, B. Type I interferon signaling in dendritic cells stimulates the development of lymph node–resident T follicular helper cells. Immunity 31, 491–501 (2009).

    Article  CAS  Google Scholar 

  38. Batten, M. et al. Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17–producing T cells. Nat. Immunol. 7, 929–936 (2006).

    Article  CAS  Google Scholar 

  39. Stumhofer, J.S. et al. Interleukin 27 negatively regulates the development of interleukin 17–producing T helper cells during chronic inflammation of the central nervous system. Nat. Immunol. 7, 937–945 (2006).

    Article  CAS  Google Scholar 

  40. Prinz, M. et al. Innate immunity mediated by TLR9 modulates pathogenicity in an animal model of multiple sclerosis. J. Clin. Invest. 116, 456–464 (2006).

    Article  CAS  Google Scholar 

  41. Steinman, L., Martin, R., Bernard, C., Conlon, P. & Oksenberg, J.R. Multiple sclerosis: deeper understanding of its pathogenesis reveals new targets for therapy. Annu. Rev. Neurosci. 25, 491–505 (2002).

    Article  CAS  Google Scholar 

  42. Durelli, L. et al. T-helper 17 cells expand in multiple sclerosis and are inhibited by interferon-beta. Ann. Neurol. 65, 499–509 (2009).

    Article  CAS  Google Scholar 

  43. Shinohara, M.L., Kim, J.H., Garcia, V.A. & Cantor, H. Engagement of the type I interferon receptor on dendritic cells inhibits T helper 17 cell development: role of intracellular osteopontin. Immunity 29, 68–78 (2008).

    Article  CAS  Google Scholar 

  44. Pirhonen, J., Siren, J., Julkunen, I. & Matikainen, S. IFN-alpha regulates Toll-like receptor–mediated IL-27 gene expression in human macrophages. J. Leukoc. Biol. 82, 1185–1192 (2007).

    Article  CAS  Google Scholar 

  45. Müller, U. et al. Functional role of type I and type II interferons in antiviral defense. Science 264, 1918–1921 (1994).

    Article  Google Scholar 

  46. Kamphuis, E., Junt, T., Waibler, Z., Forster, R. & Kalinke, U. Type I interferons directly regulate lymphocyte recirculation and cause transient blood lymphopenia. Blood 108, 3253–3261 (2006).

    Article  CAS  Google Scholar 

  47. Clausen, B.E., Burkhardt, C., Reith, W., Renkawitz, R. & Forster, I. Conditional gene targeting in macrophages and granulocytes using LysMcre mice. Transgenic Res. 8, 265–277 (1999).

    Article  CAS  Google Scholar 

  48. Heil, F. et al. The Toll-like receptor 7 (TLR7)-specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamily. Eur. J. Immunol. 33, 2987–2997 (2003).

    Article  CAS  Google Scholar 

  49. Kumar, H. et al. Essential role of IPS-1 in innate immune responses against RNA viruses. J. Exp. Med. 203, 1795–1803 (2006).

    Article  CAS  Google Scholar 

  50. van Loo, G. et al. Inhibition of transcription factor NF-κB in the central nervous system ameliorates autoimmune encephalomyelitis in mice. Nat. Immunol. 7, 954–961 (2006).

    Article  CAS  Google Scholar 

Download references

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.

Author information

Author notes

  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

Authors
  1. Angela Dann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hendrik Poeck
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrew L Croxford
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stefanie Gaupp
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Katrin Kierdorf
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Markus Knust
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dietmar Pfeifer
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Cornelius Maihoefer
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Stefan Endres
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ulrich Kalinke
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Sven G Meuth
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Heinz Wiendl
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Klaus-Peter Knobeloch
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Shizuo Akira
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Ari Waisman
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Gunther Hartmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Marco Prinz
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Corresponding author

Correspondence to Marco Prinz.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–10 (PDF 4038 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.2964

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing