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: Mayte Suárez-Fariñas, Robert Arbeit, Weiwen Jiang, Francesca S Ortenzio, Tim Sullivan, James G Krueger
• Journal: PloS one (PLoS One) Vol. 8 Issue 12 Pg. e84634 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 24386404 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-23
• Membrane Glycoproteins
• RNA, Messenger
• TLR8 protein, mouse
• Tlr7 protein, mouse
• Tlr9 protein, mouse
• Toll-Like Receptor 7
• Toll-Like Receptor 8
• Toll-Like Receptor 9

Topics

• Animals
• Dermatitis (immunology, pathology, prevention & control)
• Female
• Gene Expression Regulation (drug effects, immunology)
• Interleukin-23 (toxicity)
• Membrane Glycoproteins (antagonists & inhibitors, immunology)
• Mice
• RNA, Messenger (immunology)
• Signal Transduction (drug effects, immunology)
• Th17 Cells (immunology, pathology)
• Toll-Like Receptor 7 (antagonists & inhibitors, immunology)
• Toll-Like Receptor 8 (antagonists & inhibitors, immunology)
• Toll-Like Receptor 9 (antagonists & inhibitors, immunology)