title: TLR recognition of self nucleic acids hampers glucocorticoid activity in lupus.
abstract: 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.
authors.affiliation: Dynavax Technologies Corporation, 2929 Seventh Street, Suite 100, Berkeley, California 94710, USA.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Guiducci
authors.forename: Mei
authors.initials: M
authors.lastname: Gong
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Xu
authors.forename: Michelle
authors.initials: M
authors.lastname: Gill
authors.forename: Damien
authors.initials: D
authors.lastname: Chaussabel
authors.forename: Thea
authors.initials: T
authors.lastname: Meeker
authors.forename: Jean H
authors.initials: JH
authors.lastname: Chan
authors.forename: Tracey
authors.initials: T
authors.lastname: Wright
authors.forename: Marilynn
authors.initials: M
authors.lastname: Punaro
authors.forename: Silvia
authors.initials: S
authors.lastname: Bolland
authors.forename: Vassili
authors.initials: V
authors.lastname: Soumelis
authors.forename: Jacques
authors.initials: J
authors.lastname: Banchereau
authors.forename: Robert L
authors.initials: RL
authors.lastname: Coffman
authors.forename: Virginia
authors.initials: V
authors.lastname: Pascual
authors.forename: Franck J
authors.initials: FJ
authors.lastname: Barrat
mesh_terms: D000293:Adolescent; D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002648:Child; D003713:Dendritic Cells / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology; D007372:Interferons / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000503:physiopathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000276:immunology; D009696:Nucleic Acids / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000276:immunology*; D015854:Up-Regulation
chemical_list: D001323:Autoantibodies; D005938:Glucocorticoids; D016898:Interferon-alpha; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D009696:Nucleic Acids; C495348:TLR7 protein, human; C495371:TLR9 protein, human; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D007372:Interferons