Publication Date:
2010-06-19
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2964153/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2964153/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- 2R44AI066483-02/AI/NIAID NIH HHS/ -- P50 AR054083/AR/NIAMS 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/AI/NIAID NIH HHS/ -- R44 AI066483-02/AI/NIAID NIH HHS/ -- U19 AI082715/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/ -- England -- Nature. 2010 Jun 17;465(7300):937-41. doi: 10.1038/nature09102.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Dynavax Technologies Corporation, 2929 Seventh Street, Suite 100, Berkeley, California 94710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20559388" target="_blank"〉PubMed〈/a〉
Keywords:
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
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
