TLR recognition of self nucleic acids hampers glucocorticoid activity in lupus

• Published in: Nature (London) Vol. 465; no. 7300; pp. 937 - 941
• Main Authors: Guiducci, Cristiana, Gong, Mei, Xu, Zhaohui, Gill, Michelle, Chaussabel, Damien, Meeker, Thea, Chan, Jean H., Wright, Tracey, Punaro, Marilynn, Bolland, Silvia, Soumelis, Vassili, Banchereau, Jacques, Coffman, Robert L., Pascual, Virginia, Barrat, Franck J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.06.2010; Nature Publishing Group
• Subjects: 631/250/262/2106/2108; 631/337; 631/80/86; 692/699/249/1313/1613; Adolescent; Animals; Apoptosis; Autoantibodies - immunology; Autoimmune diseases; Biological and medical sciences; Cell receptors; Cell Survival - drug effects; Cells, Cultured; Child; Dendritic Cells - drug effects; Disease; Disease control; Disease Models, Animal; Drug therapy; Female; Flow cytometry; Genetic aspects; Glucocorticoids - pharmacology; Health aspects; Humanities and Social Sciences; Humans; Immune system; Immunosuppressive agents; Interferon-alpha - immunology; Interferons - immunology; Kinases; letter; Lupus Erythematosus, Systemic - physiopathology; Male; Medical sciences; Membrane Glycoproteins - immunology; Mice; Mice, Inbred C57BL; multidisciplinary; NF-kappa B - immunology; Nucleic acids; Nucleic Acids - immunology; Physiological aspects; Proteins; Review boards; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Science; Science (multidisciplinary); Spleen; Systemic lupus erythematosus; Toll-Like Receptor 7 - immunology; Toll-Like Receptor 9 - immunology; Transcription factors; Up-Regulation; France; United States; Human; Toll like receptor 7; Immunopathology; Connective tissue disease; Skin disease; Rodentia; Autoimmune disease; Natural immunity; Glucocorticoid; Biological activity; Toll like receptor 9; Plasmacytoid dendritic cell; Vertebrata; Mammalia; Systemic lupus erythematosus; Treatment; Mouse; Animal; Systemic disease; Nucleic acid
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature09102

Corticosteroid boost in lupus Systemic lupus erythematosus (SLE) is an autoimmune disease in which innate tolerance to self nucleic acids is broken with devastating consequences. There have been few advances in therapy in recent years, and patients are still treated mostly with strong immunosuppressives such as high-dose glucocorticoids, often causing severe side effects. In fact lupus patients require much higher glucocorticoid doses than needed in other autoimmune diseases such as rheumatoid arthritis. A possible explanation for this low sensitivity to glucocorticoids has now been identified. In SLE patients the Toll-like receptors TLR7 and TLR9, key players in innate immunity, recognize self nucleic acids on B cells and plasmacytoid dendritic cells (PDC). Now it is shown that, in SLE patients and in lupus-prone mouse strains, stimulation of PDCs by TLR7/9 reduces the immuosuppressive potency of glucocorticoids. This suggests that inhibitors of TLR7/9 signalling, such as the novel class of oligonucleotides known as immunoregulatory sequences (IRSs), could prove to be effective corticosteroid-sparing drugs. Glucocorticoids are widely used to treat patients with autoimmune diseases such as systemic lupus erythematosus (SLE), but many treatment regimens cannot maintain disease control in SLE patients. Here it is shown that the stimulation of plasmacytoid dendritic cells through toll-like receptors TLR7 and TLR9 can account for the reduced activity of glucocorticoids to inhibit the type I interferon pathway in SLE patients. Thus inhibitors of TLR7 and TLR9 signalling might prove to be effective corticosteroid-sparing drugs. 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 activity 3 , 4 . The primary anti-inflammatory mechanism of glucocorticoids is thought to be NF-κB inhibition 5 . 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 SLE 6 , promoting anti-nuclear antibodies and the production of type I interferon (IFN), both correlated with the severity of disease 1 , 7 . Following their activation by self-nucleic acid-associated immune complexes, PDCs migrate to the tissues 8 , 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.