title: Suppression of molecular inflammatory pathways by Toll-like receptor 7, 8, and 9 antagonists in a model of IL-23-induced skin inflammation.
abstract: Psoriasis is a complex inflammatory disease resulting from the activation of T helper (Th) 1 and Th17 cells. Recent evidence suggests that abnormal activation of Toll-like receptors (TLRs) 7, 8 and 9 contributes to the initiation and maintenance of psoriasis. We have evaluated the effects of TLR antagonists on the gene expression profile in an IL-23-induced skin inflammation model in mice. Psoriasis-like skin lesions were induced in C57BL/6 mice by intradermal injection of IL-23 in the dorsum. Two TLR antagonists were compared: IMO-3100, an antagonist of TLRs 7 and 9, and IMO-8400, an antagonist of TLRs 7, 8 and 9, both of which previously have been shown to reduce epidermal hyperplasia in this model. Skin gene expression profiles of IL-23-induced inflammation were compared with or without TLR antagonist treatment. IL-23 injection resulted in alteration of 5100 gene probes (fold change ≥ 2, FDR < 0.05) including IL-17 pathways that are up-regulated in psoriasis vulgaris. Targeting TLRs 7, 8 and 9 with IMO-8400 resulted in modulation of more than 2300 mRNAs while targeting TLRs 7 and 9 with IMO-3100 resulted in modulation of more than 1900 mRNAs. Both agents strongly decreased IL-17A expression (>12-fold reduction), normalized IL-17 induced genes such as beta-defensin and CXCL1, and normalized aberrant expression of keratin 16 (indicating epidermal hyperplasia). These results suggest that IL-23-driven inflammation in mouse skin may be dependent on signaling mediated by TLRs 7, 8, and 9 and that these receptors represent novel therapeutic targets in psoriasis vulgaris and other diseases with similar pathophysiology.
authors.affiliation: Laboratory for Investigative Dermatology, The Rockefeller University, New York, New York, United States of America ; Center for Clinical and Translational Science, The Rockefeller University, New York, New York, United States of America.
authors.forename: Mayte
authors.initials: M
authors.lastname: Suárez-Fariñas
authors.affiliation: Idera Pharmaceuticals, Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Arbeit
authors.affiliation: Idera Pharmaceuticals, Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Weiwen
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Laboratory for Investigative Dermatology, The Rockefeller University, New York, New York, United States of America.
authors.forename: Francesca S
authors.initials: FS
authors.lastname: Ortenzio
authors.affiliation: Idera Pharmaceuticals, Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Tim
authors.initials: T
authors.lastname: Sullivan
authors.affiliation: Laboratory for Investigative Dermatology, The Rockefeller University, New York, New York, United States of America.
authors.forename: James G
authors.initials: JG
authors.lastname: Krueger
mesh_terms: D000818:Animals; D003872:Dermatitis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D053759:Interleukin-23 / Q000633:toxicity*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000276:immunology; D051379:Mice; D012333:RNA, Messenger / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology / Q000473:pathology; D051199:Toll-Like Receptor 7 / Q000037:antagonists & inhibitors / Q000276:immunology; D051200:Toll-Like Receptor 8 / Q000037:antagonists & inhibitors / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000037:antagonists & inhibitors / Q000276:immunology
chemical_list: D053759:Interleukin-23; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; C552579:TLR8 protein, mouse; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051217:Toll-Like Receptor 9