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TLR recognition of self nucleic acids hampers glucocorticoid activity in lupus

Nature volume 465, pages 937–941 (2010)Cite this article

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Abstract

Glucocorticoids are widely used to treat patients with autoimmune diseases such as systemic lupus erythematosus (SLE)1,2. However, regimens used to treat many such conditions cannot maintain disease control in the majority of SLE patients and more aggressive approaches such as high-dose methylprednisolone pulse therapy are used to provide transient reductions in disease activity3,4. The primary anti-inflammatory mechanism of glucocorticoids is thought to be NF-κB inhibition5. Recognition of self nucleic acids by toll-like receptors TLR7 and TLR9 on B cells and plasmacytoid dendritic cells (PDCs) is an important step in the pathogenesis of SLE6, promoting anti-nuclear antibodies and the production of type I interferon (IFN), both correlated with the severity of disease1,7. Following their activation by self-nucleic acid-associated immune complexes, PDCs migrate to the tissues8,9. We demonstrate, in vitro and in vivo, that stimulation of PDCs through TLR7 and 9 can account for the reduced activity of glucocorticoids to inhibit the IFN pathway in SLE patients and in two lupus-prone mouse strains. The triggering of PDCs through TLR7 and 9 by nucleic acid-containing immune complexes or by synthetic ligands activates the NF-κB pathway essential for PDC survival. Glucocorticoids do not affect NF-κB activation in PDCs, preventing glucocorticoid induction of PDC death and the consequent reduction of systemic IFN-α levels. These findings unveil a new role for self nucleic acid recognition by TLRs and indicate that inhibitors of TLR7 and 9 signalling could prove to be effective corticosteroid-sparing drugs.

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Figure 1: Level of expression of the PDC-induced IFN signature in glucocorticoid-treated SLE patients strictly correlates with circulating blood PDCs.
Figure 2: Glucocorticoids do not affect viability of TLR7- and TLR9-activated PDCs because of its lack of activity on TLR-induced NF-κB activation.
Figure 3: TLR9 activation in vivo renders PDCs more resistant to glucocorticoid treatment.
Figure 4: PDCs from lupus-prone mice have intrinsic resistance to glucocorticoid-induced cell death compared to normal mice because of TLR7 and 9 activation by self-nucleic acid.

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Acknowledgements

We would like to thank A. O’Garra, G. Trinchieri, J.-L. Casanova and our colleagues at Dynavax Technologies for their critical reading of the manuscript. We thank S. Noonan and H. Lopez (Murigenics) for invaluable assistance with animal work. This work was supported by NIH grants P50-ARO54083-01CORT, U19-AI082715-01, The Alliance for Lupus Research, The Mary Kirkland Foundation (to V.P.) and SBIR grant 2R44AI066483-02 (to R.L.C.).

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  1. Michelle Gill

    Present address: †Present address: University of Texas, Southwestern Medical Center, Dallas, Texas 75235, USA.,

Authors and Affiliations

  1. Dynavax Technologies Corporation, 2929 Seventh Street, Suite 100, Berkeley, California 94710, USA ,

    Cristiana Guiducci, Mei Gong, Thea Meeker, Jean H. Chan, Robert L. Coffman & Franck J. Barrat

  2. Baylor Institute for Immunology Research, Dallas, Texas 75204, USA ,

    Zhaohui Xu, Michelle Gill, Damien Chaussabel, Jacques Banchereau & Virginia Pascual

  3. Texas Scottish Rite Hospital, Dallas, Texas 75219, USA ,

    Tracey Wright, Marilynn Punaro & Virginia Pascual

  4. University of Texas, Southwestern Medical Center and Children’s Medical Center, Dallas, Texas 75235, USA ,

    Tracey Wright & Marilynn Punaro

  5. Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland 20852, USA ,

    Silvia Bolland

  6. Department of Immunology, Institut Curie, 26 rue d’Ulm, 75005 Paris, France,

    Vassili Soumelis

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Contributions

C.G. and F.J.B. designed the study; C.G., M.Go., Z.X., M.Gi., T.M. and J.H.C. performed experiments; D.C., V.P., C.G. and F.J.B. collected and analysed data; S.B. provided the mice; T.W. and M.P. followed the cohort of patients and provided clinical samples; C.G., Z.X., R.L.C., V.P. and F.J.B wrote the manuscript; V.S., J.B. and R.L.C. gave conceptual advice.

Corresponding author

Correspondence to Franck J. Barrat.

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Competing interests

C.G., M.Go., T.M., J.H.C., R.L.C. and F.J.B. are full-time employees of Dynavax Technologies.

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This file contains Supplementary Figures 1-7 with legends and Supplementary Tables 1-2. (PDF 349 kb)

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Guiducci, C., Gong, M., Xu, Z. et al. TLR recognition of self nucleic acids hampers glucocorticoid activity in lupus. Nature 465, 937–941 (2010). https://doi.org/10.1038/nature09102

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