| TLR recognition of self nucleic acids hampers glucocorticoid activity in lupus. | |
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MedLine Citation:
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PMID: 20559388 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Glucocorticoids are widely used to treat patients with autoimmune diseases such as systemic lupus erythematosus (SLE). 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. The primary anti-inflammatory mechanism of glucocorticoids is thought to be NF-kappaB inhibition. 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, promoting anti-nuclear antibodies and the production of type I interferon (IFN), both correlated with the severity of disease. Following their activation by self-nucleic acid-associated immune complexes, PDCs migrate to the tissues. 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-kappaB pathway essential for PDC survival. Glucocorticoids do not affect NF-kappaB activation in PDCs, preventing glucocorticoid induction of PDC death and the consequent reduction of systemic IFN-alpha 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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Authors:
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Cristiana Guiducci; Mei Gong; Zhaohui Xu; Michelle Gill; Damien Chaussabel; Thea Meeker; Jean H Chan; Tracey Wright; Marilynn Punaro; Silvia Bolland; Vassili Soumelis; Jacques Banchereau; Robert L Coffman; Virginia Pascual; Franck J Barrat |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Nature Volume: 465 ISSN: 1476-4687 ISO Abbreviation: Nature Publication Date: 2010 Jun |
Date Detail:
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Created Date: 2010-06-18 Completed Date: 2010-06-25 Revised Date: 2011-09-26 |
Medline Journal Info:
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Nlm Unique ID: 0410462 Medline TA: Nature Country: England |
Other Details:
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Languages: eng Pagination: 937-41 Citation Subset: IM |
Affiliation:
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Dynavax Technologies Corporation, 2929 Seventh Street, Suite 100, Berkeley, California 94710, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adolescent Animals Autoantibodies / immunology Cell Survival / drug effects Cells, Cultured Child Dendritic Cells / drug effects* Disease Models, Animal Female Glucocorticoids / pharmacology* Humans Interferon-alpha / immunology Interferons / immunology Lupus Erythematosus, Systemic / physiopathology* Male Membrane Glycoproteins / immunology Mice Mice, Inbred C57BL NF-kappa B / immunology Nucleic Acids / immunology* Toll-Like Receptor 7 / immunology* Toll-Like Receptor 9 / immunology* Up-Regulation |
| Grant Support | |
ID/Acronym/Agency:
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2R44AI066483-02/AI/NIAID NIH HHS; P50 AR054083-01/AR/NIAMS NIH HHS; P50 AR054083-010001/AR/NIAMS NIH HHS; P50 AR054083-010002/AR/NIAMS NIH HHS; P50 AR054083-019001/AR/NIAMS NIH HHS; P50 AR054083-02/AR/NIAMS NIH HHS; P50 AR054083-020001/AR/NIAMS NIH HHS; P50 AR054083-020002/AR/NIAMS NIH HHS; P50 AR054083-029001/AR/NIAMS NIH HHS; P50 AR054083-03/AR/NIAMS NIH HHS; P50 AR054083-030001/AR/NIAMS NIH HHS; P50 AR054083-030002/AR/NIAMS NIH HHS; P50 AR054083-04/AR/NIAMS NIH HHS; P50 AR054083-040001/AR/NIAMS NIH HHS; P50 AR054083-040002/AR/NIAMS NIH HHS; P50 AR054083-04S1/AR/NIAMS NIH HHS; P50 AR054083-05/AR/NIAMS NIH HHS; P50 AR054083-050001/AR/NIAMS NIH HHS; P50 AR054083-050002/AR/NIAMS NIH HHS; P50-ARO54083-01CORT//PHS HHS; R44 AI066483-02/AI/NIAID NIH HHS; U19 AI082715-01/AI/NIAID NIH HHS; U19 AI082715-017348/AI/NIAID NIH HHS; U19 AI082715-017351/AI/NIAID NIH HHS; U19 AI082715-02/AI/NIAID NIH HHS; U19 AI082715-027348/AI/NIAID NIH HHS; U19 AI082715-027351/AI/NIAID NIH HHS; U19 AI082715-03/AI/NIAID NIH HHS; U19-AI082715-01/AI/NIAID NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Autoantibodies; 0/Glucocorticoids; 0/Interferon-alpha; 0/Membrane Glycoproteins; 0/NF-kappa B; 0/Nucleic Acids; 0/TLR7 protein, human; 0/TLR9 protein, human; 0/Tlr7 protein, mouse; 0/Tlr9 protein, mouse; 0/Toll-Like Receptor 7; 0/Toll-Like Receptor 9; 9008-11-1/Interferons |
| Comments/Corrections | |
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